7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands

ABSTRACT

7-Aza-bicyclo[2.2.1]-heptane and -heptene derivatives are disclosed that can be administered to a mammal, including a human, to treat disorders associated with a decrease or increase in cholinergic activity.

CROSS-REFERENCE

This application is a CON of Ser. No. 08/296,463 Aug. 25, 1994 now U.S.Pat No. 5,817,679 which is a C-I-P of PCT/US 94/03573 Apr. 1, 1994 andwhich is a C-I-P Ser. No. 08/041,445 Apr. 1, 1993, abandoned, entitled“7-Azabicyclo[2.2.1]-heptane and -heptene Derivatives as Analgesics andAnti-inflammatory agents” and PCT application no. PCT/US 94/03573, filedon Apr. 1, 1994, entitled “7-Azabicyclo[2.2.1]-heptane and -hepteneDerivatives as Analgesics and Anti-inflammatory Agents”.

This invention is in the area of 7-azabicyclo[2.2.1]heptane and -heptenederivatives and their method of manufacture and pharmaceutical use.

BACKGROUND OF THE INVENTION

Opiates, and in particular, morphine, are routinely administered for thetreatment of moderate to severe pain. Agents that are less potent thanmorphine, such as codeine, mixed agonist-antagonist opioids, andnon-opiate analgesics, including non-steroidal anti-inflammatory drugs(NSAIDS) are often used to relieve mild to moderate pain. Because of thewell-known side effects of opiates, including chemical dependence andrespiratory depression, there is a strong need for a non-opiate basedanalgesic for moderate to severe pain that would equal or exceed thepotency of opiate analgesics, yet lack the serious side effectsassociated with the administration of opiates.

Spande, et al., reported in 1992 that a potent nonopiate analgesic hadbeen isolated from the skins of the Ecuadoran poison frog, Epipedobatestricolor. Spande, et al., 1992 J. Am. Chem. Soc., 114, 3475-3478. Thestructure of the compound was determined by mass spectroscopy, infraredspectroscopy, and nuclear magnetic resonance asexo-2-(2-chloro-5-pyridyl)-7-azabicyclo [2.2.1]heptane (see FIG. 1). Thecompound, which was named epibatidine, is the first member of the classof 7-azabicyclo[2.2.1]heptane compounds to be found in nature. Limitedpharmacological evaluation of epibatidine indicated that it isapproximately 500 times more potent than morphine in eliciting theStraub-tail response, and that this effect is not reversed by the opiateantagonist naloxone. In the hot plate analgesia assay, epibatidine isapproximately 200 times as potent as morphine. It has also beendetermined that epibatidine has a negligible affinity for opiatereceptors (1/8000 times that of morphine). Based on this data, itappears that epibatidine is a very potent analgesic that acts via anon-opiate mechanism.

In 1993, it was reported that epibatidine is a nicotinic cholinergicreceptor agonist. Qian, C.; Li, T.; Shen, T. Y.; Libertine, G. L.;Eckman, J.; Biftu, T.; Ip, S. Epibatidine is a nicotinic analgesic.European J. Pharmacology, 1993, 250(3):R-13-14; Fletcher, S.; Baker, R.;Chambers, M. M.; Herbert, R. H.; Hobbs, S. C.; Thomas, S. R.; Veerler,H. M.; Watt, A. P.; Ball, R. G. Total synthesis and determination of theabsolute configuration of epibatidine. J. Org. Chem., 1994,59(7):1771-1778; Baldio, B.; Daly, J. W.; Epibatidine. A potentanalgetic and nicotinic agonist. FASEB Journal, 1994, 8(4-5):A875. Mol.Pharmacol., 1994, 45:563-569; Dukat, M.; Damaj, M. I.; Glassco, W.;Dumas, D.; May, E. I.; Martin, B. R.; Glennon, R. A. Epibatidine: A veryhigh affinity nicotine-receptor ligand. Medicinal Chem. Res., 1994,4:131-139.

Cholinergic receptors play an important role in the functioning ofmuscles, organs and generally in the central nervous system. There arealso complex interactions between cholinergic receptors and the functionof receptors of other neurotransmitters such as dopamine, serotonin andcatecholamines.

Acetylcholine (ACh) serves as the neurotransmitter at all autonomicganglia, at the postganglionic parasympathetic nerve endings, and at thepostganglionic sympathetic nerve endings innervating the eccrine sweatglands. Different receptors for ACh exist on the postganglionic neuronswithin the autonomic ganglia and at the postjunctional autonomiceffector sites. Those within the autonomic ganglia and adrenal medullaare stimulated predominantly by nicotine and are known as nicotinicreceptors. Those on autonomic effector cells are stimulated primarily bythe alkaloid muscarine and are known as muscarinic receptors.

The nicotinic receptors of autonomic ganglia and skeletal muscle are nothomogenous because they can be blocked by different antagonists. Forexample, d-tubocurarine effectively blocks nicotinic responses inskeletal muscle, whereas hexamethonium and mecamylamine are moreeffective in blocking nicotinic responses in autonomic ganglia. Thenicotinic cholinergic receptors are named the N_(M) and N_(N) receptors,respectively.

Muscarinic receptors are divided into at least four subtypes (M-1through M-4). An M-5 receptor has been cloned in human cells. The M-1receptor is localized in the central nervous system and perhapsparasympathetic ganglia. The M-2 receptor is the non-neuronal muscarinicreceptor on smooth muscle, cardiac muscle and glandular epithelium.Muscarinic receptors can be blocked by administration of atropine.Bethanechol is a selective agonist for the M-2 receptor and pirenzepineis a selective antagonist of the M-1 receptor.

In light of the fact that epibatidine is a strong cholinergic receptorligand, it would be of interest to provide new7-azabicyclo[2.2.1]-heptane and -heptene derivatives withpharmacological activity.

Therefore, it is an object of the present invention to provide new7-azabicyclo[2.2.1]-heptane and -heptene derivatives with analgesic,anti-inflammatory and other pharmaceutical activities.

It is a further object of the present invention to provide compoundswhich are cholinergic receptor ligands.

It is still another object of the present invention to provide compoundswhich are agonists and antagonists of muscarinic and nicotinicreceptors.

It is still another object of the present invention to provide newmethods for the treatment of pain.

It is another object of the present invention to provide compositionsand methods for the treatment of cognitive, neurological, and mentaldisorders, as well as other disorders characterized by decreased orincreased cholinergic function.

SUMMARY OF THE INVENTION

7-Azabicyclo[2.2.1]-heptane and -heptene compounds are disclosed ofFormula (I):

wherein:

R¹ and R⁴ are independently hydrogen, alkyl, including CH₃;alkylhydroxy, including CH₂OH; alkyloxyalkyl, including —CH₂OCH₃;alkylthioalkyl, including —CH₂SCH₃; alkylamino, including —CH₂NH₂;alkylaminoalkyl or alkylaminodialkyl, including CH₂NH(CH₃) andCH₂N(CH₃)₂; oxyalkyl, including —OCH₃; carboalkoxy, includingcarbomethoxy; allyl, aryl and thioalkyl, including —SCH₃;

R³, R⁵ and R⁶ are independently hydrogen, alkyl, including —CH₃;alkylhydroxy, including —CH₂OH; alkyloxyalkyl, including —CH₂OCH₃;alkylthioalkyl, including —CH₂SCH₃; alkylamino, including —CH₂NH₂;alkylaminoalkyl or alkylaminodialkyl, including CH₂NH(CH₃) andCH₂N(CH₃)₂; oxyalkyl, including —OCH₃; thioalkyl, including —SCH₃; halo,including Cl, F; haloalkyl, including CF₃; NH₂, alkylamino ordialkylamino, including —N(CH₃)₂ and —NHCH₃; cyclic dialkylamino,including

 amidine, cyclic amidine including

 and their N-alkyl derivatives;

 —CO₂H; CO₂alkyl, including —CO₂CH₃; —C(O)alkyl, including —C(O)CH₃;—CN, —C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, including —C(O)N(CH₃)₂;allyl, —SO₂(alkyl), —SO₂aryl, including —SO₂(C₆H₅), —S(O)alkyl,—S(O)aryl, aryl, heteroaryl;

R₅ and R₆ together can be alkylidene or haloalkylidene, including —CH₂—and —CF₂—; epoxide (—O—); episulfide (—S—); imino (—N(alkyl)— or —N(H)—)or a fused aryl or heteroaryl ring including a fused phenyl ring;

R₂ is independently hydrogen, alkyl, including CH₃; alkenyl including—CH₂—HC═CH₂; alkylhydroxy, including —CH₂—OH; alkyloxyalkyl including—CH₂—O—(alkyl), alkylamine, including —CH₂NH₂; carboxylate, C(O)Oalkyl,including CO₂Me; C(O)Oaryl, C(O)Oheteroaryl, COOaralkyl, —CN,—NHC(O)R¹², —CH₂NHC(O)R¹², Q, C(O)Q, -alkyl(Q), -alkenyl(Q),-alkynyl(Q), —O—(Q) —S—Q, —NH—Q or —N(alkyl)—Q;

R₂ and R₃ together can be —C(O)—NR⁸—C(O) or CH(OH)—N(R⁸)—C(O)— whereinR⁸ can be alkyl, aryl including phenyl, or heteroaryl;

R₇ is hydrogen, alkyl, including CH₃, or CH₂CH₃; alkyl substituted withone or more halogens, including CH₂CH₂Cl; —CH₂—(cycloalkyl), including—CH₂—(cyclopropyl); —CH₂CH═CH₂, —CH₂CH₂(C₆H₅), alkylhydroxy, includingCH₂CH₂OH, alkylamino(alkyl)₂, including CH₂CH₂N(CH₃)₂ alkyloxyalkyl,alkylthioalkyl, aryl, dialkyl to form a quarternary ammonium including

 or

wherein R⁹ is hydrogen or alkyl;

wherein Y′ is CN, NO₂, alkyl, OH, —O-alkyl;

wherein Z is O or S;

wherein R¹⁰ and R¹¹ are each independently —O, —OH, —O-alkyl, —O-aryl,—NH₂, —NH(alkyl), —N(alkyl)₂, —NH(aryl) and —N(aryl)₂;

wherein R¹² is alkyl, aryl, alkaryl, aralkyl, heteroaryl, alkenyl,alkynyl, and heteroaralkyl.

wherein the Q moiety can be optionally substituted with 1 to 3 Wsubstituents; and

W is alkyl, including CH₃; halo, including Cl and F; aryl, heteroaryl,OH, oxyalkyl, including —OCH₃; SH, thioalkyl, including —SCH₃;—SO(alkyl) including —SOCH₃; —SO₂alkyl, including —SO₂CH₃; —OCH₂CH═CH₂,—OCH₂(C₆H₅), CF₃, CN, alkylenedioxy, including -methylenedioxy-; —CO₂H,—CO₂alkyl, including —CO₂CH₃; —OCH₂CH₂OH, —NO₂, —NH₂, —NH(alkyl),including —NHCH₃; —N(alkyl)₂, including —N(CH₃)₂; —NHC(O)alkyl,including —NHC(O)CH₃; —SO₂CF₃, or —NHCH₂aryl, including —NHCH₂(C₆H₅);—C(O)alkyl; —C(O)aryl; —C(O)aralkyl; —C(O)alkaryl; —C(O)heteroaryl;—P(O)₂O⁻M⁺ wherein M is a pharmaceutically acceptable cation; andwherein

the - - - indicates an optional double bond.

These compounds are cholinergic receptor ligands, and thus act asnicotinic or muscarinic agonists or antagonists. Therefore, thecompounds can also be used in the treatment of cognitive, neurological,and mental disorders, as well as other disorders characterized bydecreased or increased cholinergic function.

The selectivity of the selected compound for for various receptorsubtypes is easily determined by routine in vitro and in vivopharmacological assays known to those skilled in the art, and describedin more detail below. The receptor subtype selectivity is expected tovary based on the substituents on the 7-aza-norbornane or norbornenering.

Compounds that act as nicotinic receptor agonists have central orperipheral analgesic activity, and, or alternatively, anti-inflammatoryactivity, and thus can be administered to a mammal, including a human,to treat pain and inflammatory disorders. A method for the treatment ofpain is also presented that includes administering an effective amountof the compound or its pharmaceutically acceptable salt or derivative,or mixtures thereof, to a host in need of analgesic therapy, optionallyin a pharmaceutically acceptable carrier or diluent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an illustration of the chemical structure ofexo-2-(2-chloro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (epibatidine).

FIGS. 2a and 2b are schematic illustrations of processes for thepreparation of active compounds through the Diels-Alder reaction of anN-(electron withdrawing substituted)pyrrole with anarylsulfonyl(optionally substituted aryl or heterocyclic)acetylene.

FIG. 3 is a schematic illustration of the synthesis of 7-aza-2-[oxazoleand oxadiazole]-bicyclo[2.2.1]heptane fromexo-2-carbomethoxy-7-methyl-7-azanorbornane.

FIG. 4 is a schematic illustration of the synthesis of7-aza-2-[heterocycles]-bicyclo[2.2.1]heptane fromexo-2-cyano-7-methyl-7-azanorbornane.

FIG. 5 is a schematic illustration of the conversion ofexo-2-carbomethoxy-7-methyl-7-azanorbornane andexo-2-cyano-7-methyl-7-azanorbornane to 7-methyl-7-aza-2-[methylaminoand methylacetamido]-bicyclo[2.2.1]heptane.

FIG. 6 is a schematic illustration of the synthesis of7-methyl-7-aza-2-[isoxazolyl]-bicyclo[2.2.1]heptane.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

The term alkyl, as used herein, refers to a saturated straight,branched, or cyclic (or a combination thereof) hydrocarbon of C₁ to C₁₀,and specifically includes methyl, ethyl, propyl, isopropyl,cyclopropylmethyl, cyclobutylmethyl, butyl, isobutyl, t-butyl, pentyl,cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, heptyl, octyl,nonyl, and decyl.

The term lower alkyl, as used herein, refers to a C₁ to C₆ saturatedstraight, branched, or cyclic (in the case of C₅₋₆) hydrocarbon, andspecifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, cyclopropylmethyl, pentyl, cyclopentyl, cyclobutylmethyl,isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl.

The term alkylamino refers to an amino group that has an alkylsubstituent.

The term alkynyl, as referred to herein, refers to a C₂ to C₁₀ straightor branched hydrocarbon with at least one triple bond.

The term lower alkynyl, as referred to herein, refers to a C₂ to C₆alkynyl group, specifically including acetylenyl and propynyl.

The term aryl, as used herein, refers to phenyl, or substituted phenyl,wherein the substituent is halo, alkyl, alkoxy, alkylthio, haloalkyl,hydroxyalkyl, alkoxyalkyl, methylenedioxy, cyano, C(O)(lower alkyl),carboxy, CO₂alkyl, amide, amino, alkylamino and dialkylamino, andwherein the aryl group can have up to 3 substituents.

The term halo, as used herein, includes fluoro, chloro, bromo, and iodo.

The term aralkyl refers to an aryl group with an alkyl substituent.

The term alkaryl refers to an alkyl group that has an aryl substituent,including benzyl, substituted benzyl, phenethyl or substitutedphenethyl, wherein the substituents are as defined for aryl groups.

The term heteroaryl or heteroaromatic, as used herein, refers to anaromatic moiety that includes at least one sulfur, oxygen, or nitrogenin the aromatic ring. Nonlimiting examples are furyl, pyridyl,pyrimidyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl,quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl,isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl,quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl,quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, and pyrazolopyrimidinyl.

The term organic or inorganic anion refers to an organic or inorganicmoiety that carries a negative charge and can be used as the negativeportion of a salt.

The term “pharmaceutically acceptable cation” refers to an organic orinorganic moiety that carries a positive charge and that can beadministered in association with a pharmaceutical agent, for example, asa counteraction in a salt.

The term enantiomerically enriched composition or compound” refers to acomposition or compound that includes at least 95%, and typically 98,99, or 100 by weight of a single enantiomer of the compound.

The term pharmaceutically active derivative refers to any compound thatupon administration to the recipient, is capable of providing directlyor indirectly, the compounds disclosed herein.

As used herein, the term dipolarophile refers to a compound or moietythat reacts with a dipolar species to form a cycloaddition product.

As used herein, the term dienophile refers to a compound or moiety thatreacts with a diene to form a cycloaddition product.

As used herein, the term η refers to a pi-orbital complex of anunsaturated compound with a metal, and wherein the superscript after theη refers to the number of sp² carbon atoms bonded to the metal.

The term electron withdrawing substituent as used herein refers to asubstituent that pulls electron density from the moiety to which it isattached through induction or resonance. A wide variety of electronwithdrawing substituents are well known to those skilled in organicsynthesis.

II. Examples of Active Compounds

7-Azabicyclo[2.2.1]-heptane and -heptene derivatives of Formula (I) areprovided that are cholinergic receptor ligands. These compoundstypically act as nicotinic or muscarinic receptor agonists orantagonists. The compounds can be used in the treatment of cognitive,neurological, and mental disorders, as well as other disorderscharacterized by decreased or increased cholinergic function.

Some of the compounds have central and peripheral analgesic and, oralternatively, anti-inflammatory activity, and thus can be administeredto a mammal, including a human, to treat pain and inflammation. A methodfor the treatment of pain is also presented that includes administeringan effective amount of the compound or its pharmaceutically acceptablesalt or derivative, or mixtures thereof, to a host in need of analgesictherapy, optionally in a pharmaceutically acceptable carrier or diluent.

The numbering scheme for 7-azabicyclo [2.2.1]-heptane and -heptenederivatives is as illustrated below.

The 7-azabicyclo[2.2.1]-heptanes and -heptenes disclosed herein canexhibit a number of stereochemical configurations. As discussed above,the compounds are prepared in a Diels-Alder cycloaddition reaction of adienophile with a pyrrole, or a modification of the Diels Alder reactioninvolving the reaction of a dipolarophile with a pentaammineosmium(II)activated pyrrole. In the transition state of the cycloadditionreaction, there are two possible relative orientations of the diene ordienophile, referred to as endo and exo. Endo configurations are formedwhen other unsaturated groups in the dienophile (or dipolarophile) lienear the developing double bond in the diene. Exo configurations areformed when other unsaturated groups in the dienophile (ordipolarophile) lie away from the developing double bond in the diene.Depending on the substitution on the carbon atoms, the endo and exoorientations can yield different stereoisomers.

Carbon atoms 2, 3, 5 and 6 in 7-azabicyclo[2.2.1]heptanes and carbonatoms 2 and 3 or 5 and 6 in 7-azabicyclo[2.2.1]heptenes are chiral whenattached to different substituents. If at least one of the carbons inthe molecule are chiral, the unsymmetrically substituted bicycliccompounds exist as one or more diastereomeric pairs. The R groups in theactive compounds described herein can also include chiral carbons, andthus, optically active centers.

It is sometimes found that one or more enantiomers of a biologicallyactive compound is more active, and perhaps less toxic, than otherenantiomers of the same compound. Such enantiomerically enrichedcompounds are preferred for pharmaceutical administration to humans orother hosts.

One of ordinary skill in the art can easily separate the enantiomers ofthe disclosed compounds using conventional processes, and can evaluatethe biological activity of the isolated enantiomers using methodsdisclosed herein or otherwise known. Through the use of chiral NMR shiftreagents, polarimetry, or chiral HPLC, the optical enrichment of thecompound can be determined.

Classical methods of resolution include a variety of physical andchemical techniques. For example, since the compound has a basic amine(N⁷), it can be reacted with a chiral acid to form diastereomeric saltsthat may possess significantly different solubility properties.Nonlimiting examples of chiral acids include malic acid, mandelic acid,dibenzoyl tartaric acid, 3-bromocamphor-B-sulfonic acid,10-camphorsulfonic acid, and di-p-toluoyltartaric acid, and (−)-menthylchloroformate. Similarly, acylation of a free amine or hydroxyl group inthe molecule with a chiral acid also results in the formation of adiastereomeric amide or ester whose physical properties may differsufficiently to permit separation. Enantiomerically pure or enrichedcompounds can be also obtained by passing the racemic mixture through achromatographic column that has been designed for chiral separations,including cyclodextrin bonded columns marketed by Rainin Corporation.

Chiral benzylated pyrrole complexes such as[Os(NH₃)₅(²—(ArRHC-(pyrrole)))]²⁺) can be used for enantioselectivesyntheses of 7-azanorbornanes.

The following are nonlimiting examples of specific compounds that fallwithin the scope of the invention. These examples are merely exemplary,and are not intended to limit the scope of the invention.

(A) Epibatidine isomers:

1-7-aza-2-exo-(2-chloro-5-pyridyl)-bicyclo[2.2.1]heptane and itspharmaceutically acceptable salts, including the hydrochloride salt;1-7-aza-2-exo-(2-chloro-5-pyridyl)-bicyclo[2.2.1]heptane and itspharmaceutically acceptable salts, including the hydrochloride salt;

d and 1-7-aza-endo-(2-chloro-5-pyridyl)-bicyclo[2.2.1]heptane and itspharmaceutically acceptable salts, including the hydrochloride salts;

(B) d and 1 enantiomers of the 7-aza-bicyclo[2.2.1]heptane derivativescontaining the following substituents:

A combination of 7-methyl, 7-allyl-, 7-cyclopropylmethyl,7-cyclobutylmethyl, 7-phenethyl, 7-hydroxyethyl, 7-methoxyethyl,7-methylthioethyl, 7-dimethylaminopropyl, 7-formamidinyl,7-(2-chloroethyl), 7-disodium phosphate and 7-(4-methoxybenzyl)substituents with a 2-exo-(2-chloro-5-pyridyl) substituent;

2-exo-(3-pyridyl); 2-endo-(3-pyridyl); 7-methyl-2-exo-(3-pyridyl);7-cyclopropylmethyl-2-exo-(3-pyridyl); 7-phenethyl-2-exo-(3-pyridyl);

2-exo-(4-pyridyl); 7-methyl-2-exo-(4-pyridyl);7-allyl-2-exo-(4-pyridyl); 7-cyclopropylmethyl-2-exo-(4-pyridyl);

2-exo-(3-chloro-4-pyridyl);7-cyclopropylmethyl-2-exo-(3-chloro-4-pyridyl);7-phenethyl-2-exo-(3-chloro-4-pyridyl) 2-exo-(2chloro-3-pyridyl);2-exo-(2-chloro-4-pyridyl);

2-exo-(2-fluoro-5-pyridyl); 2-exo-(2-methoxy-5-pyridyl);2-exo-(2-methylthio-5-pyridyl); 2-exo-(2-methyl-5-pyridyl);2-exo-(2-dimethylamino-5-pyridyl); 2-exo-(2-hydroxy-5-pyridyl) and their7-cyclopropylmethyl derivatives;

The exo and endo isomers of:

2-phenyl; 2-(3-chlorophenyl); 2-(3-dimethylaminophenyl);2-(3-trifluoromethylphenyl); 2-(3,4-methylenedioxyphenyl);2-(3,4-dimethoxyphenyl); 2-(4-fluorophenyl); 2-(4-hydroxyphenyl);2-(4-methylthiophenyl); 2-(4-methylsulfonylphenyl),2-(3,5-difluorophenyl); 2-(2-chlorophenyl); 2-(2-naphthyl);2-(7-methoxy-2-naphthyl); 2-(5-chloro-2-thienyl);2-(chloro-5-thiazolyl); 2-(4-pyrimidyl); 2-(2-chloro-5-pyrimidyl);2-(5-chloro-2-pyridazinyl); 2-(1,2,5-thiadiazol-3-yl);2-(5-dimethylamino-2-furyl); 2-(5-indolyl); 2-(5-fluoro-3-indolyl);2-(5-methoxy-3-indolyl); 2-(4-chlorobenzyl);2-(5-chloro-3-pyridylmethyl); 2-(4-pyridylmethyl); 2-nicotinyl;2-(6-chloronicotinyl); 2-isonicotinyl; 2-(3-chloro-isonicotinyl);2(4-chlorobenzoyl); 2-(4-dimethylaminobenzoyl); 2-(3,4-dimethoxybenzoyl)and their 7-methyl, 7-cyclopropylmethyl, 7-allyl and 7-phenethylderivatives.

(C) The exo and endo isomers of7-aza-2-(2-chloro-5-pyridyl)-bicyclo[2.2.1]heptane containing thefollowing substituents at the 1, 2, 3, 4, 5 or 6 positions:

1 or 4-methyl; 1 or 4-hydroxymethyl; 1 or 4-methoxymethyl; 1 or4-carbomethoxy; 1 or 4-allyl; 1 or 4-benzyl; 1 or 4-(4-fluorobenzyl); 1or 4-(4-methoxybenzyl); 1,4-dimethyl; 1,4-bis(hydroxymethyl);1,4-bis(methoxymethyl); 1,6 or 4,5-butylidene;

Endo or exo-3-methyl; 3-hydroxymethyl; 3-methoxymethyl; 3-carbomethoxy;3-carboxy; 3-carbamyl; 3-cyano; 3-acetyl; 3-aminomethyl;3-dimethylaminomethyl; 3-methylthiomethyl; 3-phenylsulfonyl;3-methanesulfonyl; 3-benzyl; 3-allyl; 3-cyano-1,4-dimethyl;3-hydroxymethyl-1,4-dimethyl, 3-methoxymethyl-1,4-dimethyl;3-methylthiomethyl-1,4-dimethyl; 5,6-bis(trifluoromethyl); 5 or6-methoxy; 5 or 6-methyl; 5,6-dimethyl; 5,6-dicarbomethoxy;5,6-bis(hydroxymethyl); 5,6-bis(methoxymethyl); 5 or 6-chloro; 5 or6-hydroxy; 5,6-dehydro; 5,6-dehydro-1,4-dimethyl; 3,3-dimethyl;2-methyl; 2,3-dimethyl, 5,6-methylene;

and their corresponding 7-methyl, 7-cyclopropylmethyl, 7-allyl,7-phenethyl and 7-(4-fluorobenzyl) derivatives.

(D) 7-Aza-2-(2-chloro-5-pyridyl)-bicyclo[2.2.1]hept-2-ene and its7-methyl, 7-allyl, 7-cyclopropylmethyl, 7-phenethyl and7-(4-methoxyphenethyl) derivatives; and

the corresponding 1,4-dimethyl; 1 or 4-methyl; 5,6-dimethyl and5,6-bis(trifluoromethyl) analogs.

(E) Benzo[5a,6a]epibatidine and its N-methyl derivative;2,3-dehydroepibatidine; 5,6-bis(trifluoromethyl)deschloroepibatidine;2-carbomethoxy-7-methyl-7-azabicyclo[2.2.1]heptane;2-cyano-7-methyl-7-azabicyclo[2.2.1]heptane;trans-2,3-bis-carbomethoxy-7-azabicyclo[2.2.1]-heptane;exo-2-amino-7-methyl-7-azabicyclo[2.2.1]-heptane;exo-2-(1-pyrrolylmethyl)-7-methyl-7-azabicyclo [2.2.1]heptane;exo-2-hydroxymethyl-7-methyl-7-azabicyclo[2.2.1]heptane;exo-2-hydroxymethyl-7-methyl-2-azabicyclo[2.2.1]heptane.

(F) exo-2-acetamidomethyl-7-methyl-7-azabicyclo[2.2.1]heptane;exo-2-benzamidomethyl-7-methyl-7-azabicyclo[2.2.1]heptane;N-[exo-2-(7-methyl-7-azabicyclo[2.2.1]heptyl)methyl]-N¹-phenyl urea;exo-2,5′-(3′-methyl-1′,2′,4′-ozadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane;exo-2,5′-(3′-methyl-1′,2′,4′-oxadiazolyl)-1,4-dimethyl-7-azabicyclo[2.2.1]heptane;endo-2,5′-(3′-methyl-1′,2′,4′-oxadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane;exo-2,5′-(3′-[4′-methoxyphenyl]-1′,2′,4′-oxadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane;endo-2,2′-(5′-methyl-1′,3′,4′-oxadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane;exo-2,2′-(5′-methyl-1′,3′,4′-oxadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane;2-carbomethoxy-7-(3′,5′-dimethylbenzyl)-7-azabicyclo[2.2.1]heptane;2-carbomethoxy-7-azabicyclo[2.2.1]heptane;(+/−)-(exo)-7-(1,1-dimethylethoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one;(+/−)-7-(1,1-dimethyl-ethoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ylidene;(+/−)-(exo)-7-(1,1-dimethylethoxycarbonyl)-2-hydroxymethyl-7-azabicyclo[2.2.1]heptane;(+/−)-(exo)-7-(1,1-dimethylethoxycarbonyl)-2-formyl-7-azabicyclo[2.2.1]heptane;(+/−)-(exo)-2-[1′-(2′,2′-dibromo-1′-ethenyl)]-7-(1,1-dimethylethoxycarbonyl)-7-azabicyclo[2.2.1]heptane;(+/−)-(exo)-2-(1′-ethynyl)-7-(1,1-dimethylethoxycarbonyl)-7-azabicyclo[2.2.1]heptane;(+/−)-7-(dimethylethoxycarbonyl)-2-[5′-(3′-methyl)isoxazolyl]-7-azabicyclo[2.2.1]heptane;2-[5′-(3′-methyl)isoxazolyl]-7-azabicyclo[2.2.1]heptane;2-[5′-(3′-methyl)isoxazolyl]-7-azabicyclo[2.2.1]heptane;(+/−)-(exo)-7-(methoxycarbonyl)-2-(2′-quinolyl)-7-azabicyclo[2.2.1]heptane;(+/−)-(exo)-2-(2′-quinolyl)-7-azabicyclo[2.1.1]heptane;(+/−)-(exo)-7-methyl-2-(2′-quinolyl)-7-azabicyclo[2.2.1]heptane;2-(5′-oxazole)-7-methyl-7-azanorbornane;2-(1′,3′,4′-oxadiazole)-7-methyl-7-azanorbornane;2-(tetrazole)-7-methyl-7-azanorbornane;2-(imidazole)-7-methyl-7-azanorbornane;2-(benzopyrimidinone)-7-methyl-7-azanorbornane;2-(acylamino)-7-methyl-7-azanorbornane and2-(acylaminomethyl)-7-methyl-7-azanorbornane.

III. Methods for the Synthesis of Optionally Substituted7-Azabicyclo[2.2.1]-heptanes and -heptenes

A. Synthesis of the 7-Azabicyclo[2.2.1]-Heptane or -Heptene Ring Systemfrom Pyrroles Via Pentaammineosmium(II) Complexes

It has been discovered that 7-azabicyclo[2.2.1]-heptane and -heptenederivatives can be prepared by combining a dipolarophile with anoptionally substituted pyrrole that has been complexed withpentaammineosmium(II).

Any dipolarophile can be used in this reaction that reacts with thepentaammineosmium pyrrole complex to provide an optionally substituted7-azabicyclo[2.2.1]-heptene, which is easily converted to thecorresponding 7-azabicyclo[2.2.1]-heptane. Examples of dipolarophilesinclude compounds of the structure Z₁—C═C—Z₂, wherein Z₁ and Z₂ areindependently electron withdrawing groups, including without limitation,esters, nitriles, ketones, aldehydes, amides, —NO₂, sulfones,anhydrides, —CF₃, pyridinium salts, and for example, CO(alkyl, aryl orheteroaryl), C(O)H, CO₂(alkyl, aryl, or heteroaryl), SO₂(alkyl, aryl, orheteroaryl), or wherein Z₁ and Z₂ are together (CO)₂O, or (CO)₂N.Specific compounds include N-methylated and 6-carboxylated pyridylacrylates, alkyl acrylate, alkyl methacrylate, pyridyl substituted vinylsulfones, acrylonitriles, anhydrides, maleimides,alpha-methylene-δ-butyrolactone, maleates, and fumarates.

Analogously, any optionally substituted pyrrole can be used that oncomplexation with pentaammineosmium(II) will react with a dipolarophile.Examples of suitable pyrroles include 2,5-dialkylpyrrole,2-alkylpyrrole, 3-alkylpyrrole, 1-alkylpyrrole, 3,4-dialkylpyrrole,pyrrole, 1-silylated pyrrole, (1, 2, or 3)alkoxy or amino pyrrole,2,3-dialkoxypyrrole, 2,5-dialkoxypyrrole, and 3,4-dialkoxypyrrole.

As shown below in Scheme 1, a complex is readily formed between pyrroleand the π-base pentaammineosmium(II) in which the osmium coordinates theheterocycle across C2 and C3. At 20° C., this species is in equilibriumwith its linkage isomer in which the metal binds across C3 and C4.Although the 3,4-η species is only a minor component (▴G_(iso)>3kcal/mol), the metal coordination in this species renders the remainingportion of the pyrrole an azomethine ylide(R₂C⁺—N(R)—C—R₂⇄R₂C═N⁺(R)—CR₂), and thereby dramatically enhances thetendency of the ligand to undergo a 1,3-dipolar cycloaddition withsuitable dipolarophiles.

The resulting 7-azabicyclo[2.2.1]hept-5-ene ligand is unstable withrespect to cycloreversion, but metal coordination greatly stabilizes thecomplex and thus provides the opportunity to carry out functional grouptransformations while keeping the bicyclic framework intact. Forexample, derivatization of electron-withdrawing groups in the 2- or3-positions of the norbornene framework, using conventional processes,provides a wide array of functionalized 7-azanorbornenes. specifically,as shown in Scheme 2 below, the exo-carbonyl cycloadduct complex 2,prepared in a one-pot synthesis from 2,5-dimethylpyrrole, is reduced tothe corresponding alcohol and oxidatively decomplexed to yield therelatively inaccessible 5-hydroxymethyl-7-azanorbornene 3.

This approach can be used to construct the epibatidine ring system if a3-vinyl pyridine is used as the dipolarophile. The use ofmethyl-trans-3-(3-pyridyl)-acrylate in the above reaction sequence(using the 2,5-dimethylpyrrole complex shown in Scheme 2), yieldscompound 4, shown below, which contains the carbon skeleton of thenatural product.

Epibatidine has no substitution at the bridgehead carbons (C¹ and C⁴).The reactivity of simple pentaammineosmium(II)-pyrrole complexes withdipolarophiles decreases in the order2,5-dimethylpyrrole>N-methylpyrrole>pyrrole. Generally, additionalactivation of the dipolarophile, by careful selection of the electronwithdrawing group attached to the olefin, or high pressure is requiredto obtain cycloadducts without substitution at the bridgehead positions.Although the parent pyrrole complex gives complex mixtures, the N-methylpyrrole reacts with the N-methylated and 6-carboxylated pyridylacrylates to yield cycloadducts 5 and 6 as single diastereomers.

An alternative method for stabilization of the azabicyclo[2.2.1]heptanenucleus involves protonation of the secondary amine (and pyridyl group)followed by oxidative removal of the metal and in situ hydrogenation ofthe azanorbornene. An example of this method is shown in Scheme 3 belowfor the synthesis of the1,4-dimethyl-exo-carbomethoxy-norchloroepibatidine 7.

The process for preparing optionally substituted7-azabicyclo[2.2.1]heptanes and 7-azabicyclo[2.2.1]hept-5-enes viapentaammineosmium(II) complexes proceeds in three steps. In the firststep, the optionally substituted pyrrole is treated withpentaammineosmium(II). An excess of the pyrrole complex is usuallypreferred. Pentaammineosmium(II) is generated in situ by the reductionof pentaammineosmium(III) with a one electron reducing agent that has areducing potential of less than −0.75 volts versus hydrogen. Thecounteranion of pentaammineosmium (II) can be any anion that does notadversely affect the overall reaction. Typical counteranions are CF₃SO₃⁻ (Otf⁻), PF₆, X⁻, and (alkyl or aryl)SO₃ ⁻.

Any chemical or electrochemical reducing agent that can reduce theosmium complex from a III valence state to a II valence state and whichdoes not cause or participate in undesired side reactions is suitable.Examples of appropriate reducing agents include magnesium, zinc,aluminum, sodium, cobaltocene and electrochemical reduction. In apreferred embodiment, activated magnesium powder is used.

The optionally substituted pyrrole, pentaammineosmium(III), and reducingagent are stirred at a temperature ranging between 0° C. and 50° C.until the desired organometallic complex is formed, typically between0.1 and 1.0 hours. The reaction can be carried out in a polar ornonpolar solvent, including but not limited to N,N-dimethylacetamide,N,N-dimethylformamide, water, methanol, acetonitrile, acetone,dimethylsulfoxide, CH₂Cl₂, or dimethoxyethane. The reaction is carriedout in the absence of O₂, and typically under nitrogen, at a pressure of1 atm or greater.

In the second step of the process, the dipolarophile is added to thestirring solution of the pyrrole pentaammineosmium (II) complex toproduce an optionally substituted 7-azabicyclo[2.2.1]hept-5-ene. Anymolar ratio of dipolarophile to pyrrole can be used that provides thedesired results. Typically, a molar ratio of dipolarophile to pyrroleranging between approximately 1 and 10 provides a suitable yield ofproduct. The reaction solution is stirred at a temperature rangingbetween 10 and 50° C. until the product is formed, typically between 1and 24 hours.

In an optional step after the bicyclic ring system is formed, and whilepentaammineosmium is still complexed to the pi-orbital of the heptenemoiety, functional groups on the bicyclic ring can be derivatized usingconventional processes. For example, esters can be reduced to alcohols,nitriles to amines, sulfones to sulfides, nitro groups to amines, andamides to amines. Sulfones and carboxylates can be reductivelyeliminated using the Barton decarboxylation procedure. High temperaturesand strong bases should be avoided in the functionalization proceduresto avoid ring disruption and unwanted side reactions.

In the third step of the reaction, the pentaammineosmium (II) complex isremoved from the optionally substituted 7-azabicyclo[2.2.1]hept-5-eneby, for example, treatment with cerium (IV) or oxygen in acidicsolution. For example, the 7-azabicyclo[2.2.1]hept-5-ene can be treatedwith one equivalent of cerium reagent at 20° C. in a polar solvent suchas acetonitrile. Appropriate reagents include Ce(NO₃)₆(NH₄)₂, DDQ, andother inorganic or organic oxidants with E>+0.70 volts versus hydrogen.Alternatively, the osmium reagent can be removed by heating the complexas necessary, usually between approximately 50° C. and 100° C.

Using the method of synthesis described above, a wide variety ofsubstituted 7-azanorbornanes and 7-azanorbornenes can be prepared.Examples of representative compounds are summarized in Tables 1 and 2.

Some of them are useful as intermediates for the synthesis of desiredcompounds containing complex heteroaryl or polar substituents as R₂and/or R₃.

TABLE 1

R₁ R₂ R₃ 7-azabicyclo[2.2.1]heptane H exo-CH₂OH H H exo-CH₂OH₃ H Hexo-CH₂OH endo-3-py H exo-CO₂CH₃ endo-3-py H exo-CO₂CH₃ exo-3-py Hexo-SO₂Ph endo-3-py H endo-SO₂Ph exo-3-py 7-azabicyclo[2.2.1]hept-5-eneH exo-CH₂OH H CBz exo-CH₂OH H Cbz exo-OCBz H H exo-CH₂OH endo-3-py

TABLE 2

Example R₁ R₂ R₃ 15 CH₃ exo-COOMe H 15 CH₃ endo-COOMe H 16 CH₃ exo-C≡N H16 CH₃ endo-C≡N H 17 H exo-COOMe endo-COOMe 18 H exo- —C(O)—N(Ph)—C(O)—18 H endo- —C(O)—N(Ph)—C(O)— 19 Et exo- —C(O)—N(Ph)—C(O)— 20 H exo-—C(O)—N(Ph)—C(O)— 21 CH₃ exo-CH₂NH₂ H 22 CH₃ exo-CH₂NC₄H₄ H 23 CH₃exo-CH₂OH H 24 CH₃ exo-CH₂OOCPh H 25

Methods for preparing compounds of Formula (I) via derivatization of a5,6-η²-7-aza-bicyclo[2.2.1]hept-5-ene are set out below. These examplesare merely illustrative, and are not intended to limit the scope of theinvention.

EXAMPLE 1 Preparation of1,4-Dimethyl-2-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]hept-5-ene (8)

A solution of the 5,6-η² osmium complex of compound 8 (727 mg, 1.0 mmol)in 2 grams acetonitrile was protonated with excess triflic acid (250 mg,1.67 mmol) and treated at −10° C. with a likewise-cooled solution ofceric ammonium nitrate (560 mg, 1.02 mmol) and triflic acid (560 mg,3.73 mmol) in 2 grams acetonitrile. Water (1-2 ml) was added to dissolvethe precipitated salts, the mixture made basic with 40 ml 10% aqueoussodium carbonate and the product extracted with 5×20 ml methylenechloride. The extract was dried over MgSO₄ and the solvent evaporated,yielding 147 mg of brown oil. The crude product was purified by silicagel column chromatography using 1:10 of 15 wt % NH₃ inmethanol/methylene chloride, yielding 62 mg (41%) of pure 8. (oil,R_(f)=0.5). ¹H NMR (300 MHz, CDCl₃) d 6.31 (d, J=5.3 Hz, 1H), 6.09 (d,J=5.3 Hz, 1H), 3.99 (dd, J=10.3, 2.1 Hz, 1H), 3.67 (dd, J=10.3, 2.1,1H), 3.6-2.8 (v br, ˜2H, OH and NH), 1.4-1.8 (m, 3H), 1.48 (s, 3H), 1.47(s, 3H); ¹³C NMR (75 MHz, CDCl₃) d 145.2 (CH), 141.5 (CH), 69.9 (C),67.0 (C), 61.5 (CH₂), 41.7 (CH), 37.0 (CH₂), 18.9 (CH₃), 15.7 (CH₃).This material was further characterized by conversion to the picratesalt. m.p. 186-188° C.; Anal. Calcd. for C₁₅H₁₈N₄O₈: C, 47.12; H, 4.75;N, 14.65. Found: C, 46.96; H, 4.52; N, 14.66.

EXAMPLE 2 Preparation ofN-CBZ-1,4-Dimethyl-2-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]hept-5-ene(9) andN,O-Bis-CBZ-1,4-Dimethyl-2-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]hept-5-ene(10)

The crude aminoalcohol 8 obtained from 1.0 mmol of the osmium complex asdescribed above was suspended in a solution of aqueous Na₂CO₃ (0.38grams in 2 grams water), and the mixture chilled to 0° C. Benzylchloroformate (510 mg, 3 mmol) was added, and the mixture allowed towarm to room temperature with vigorous stirring. After 20 hours at 25°C. the mixture was extracted with methylene chloride, and the extractsdried and rotoevaporated, yielding 0.4 grams of brown oil. The crudematerial was chromatographed twice using 1:8 ethyl acetate/petroleumether, yielding 43 mg (10%) of 9 and 64 mg (22%) of 10 (R_(f)=0.5 and0.1, respectively) For 9: ¹H NMR(300 MHz, CDCl₃) d 7.32 (m, 5H, Phenyl),6.06 (ABq, J=5.7 Hz, 2H, H5 and H6), 5.04 (s, 2H, OCH₂Ph), 3.69 (m, 2H,CH₂OH), 2.18 (br s, 1H, OH), 1.75 (2×s, 6H, CH₃), 1.7 (m, overlap, 1H),1.55 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) d 155.2 (CO), 140.5 (CH, C5 orC6), 140.2 (CH, C6 or C5), 136.4 (C, ipso), 128.3 (CH), 127.9 (CH),127.8 (CH), 71.1 (C), 69.0 (C), 66.4 (CH₂OH), 63.0 (CH₂), 45.6 (CH),37.7 (CH₂), 19.4 (CH₃), 16.8 (CH₃). For 10: ¹H NMR(300 MHz, CDCl₃) d7.37 (m, 5H, Phenyl), 7.32 (m, 5H, Phenyl), 6.07 (ABq, J=5.5 Hz, 2H, H5and H6), 5.16 (s, 2H, OCH₂Ph), 5.05 (ABq, J=13.5 Hz,2H, OCH₂Ph), 4.33(dd, J=10.5, 7 Hz, 1H, 1/2 CH₂OCBZ), 4.06 (dd, J=10.5, 7.5 Hz, 1H,1/2CH₂OCBZ) 1.94 (m, 1H, H2), 1.79 (s, 3H, CH₃) 1.75 (s, 3H, CH₃), 1.60(dd, J=11.4, 9 Hz, 1H, H3_(endo)), 1.4 (dd, J=11.4, 3.6 Hz, H3_(exo))¹³C NMR (75 MHz, CDCl₃) d 155.0 (CO), 154.9 (CO), 140.5 (CH, C5 or C6),140.5 (CH, C6 or C5), 136.4 (C, ipso), 135.2 (C, ipso), 128.5 (overlapof 2×CH), 128.4 (CH), 128.3 (CH), 128.0 (CH), 127.8 (CH), 70.8 (C), 69.6(overlap of 2×CH₂), 68.9 (C), 66.3 (CH₂O), 43.2 (CH, C5), 38.7 (CH₂,C6), 19.3 (CH₃), 17.0 (CH₃).

EXAMPLE 3 Preparation of1,4-Dimethyl-2-endo-(3′-pyridyl)-3-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]hept-5-ene(11)

The corresponding 5,6-η² osmium complex was treated as described abovefor compound 8. Diagnostic ¹H NMR information: 6.43 (d, J=6H, 1H, H5 orH6), 6.0 (d, J=6 Hz, 1H, H6 or H5), 4.0 (dd, J=10,2.5 Hz, 1H, 1/2CH₂OH), 3.75 (dd, J=10, 2.5 Hz, 1/2 CH₂OH), 1.55 (s, CH₃), 1.38 (s,CH₃).

EXAMPLE 4 Preparation of1,4-Dimethyl-2-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane (12)

A sample of crude compound 8 (85 mg, 0.56 mmol) was stirred with 30 mg10% Pd-on-C and 0.5 g methanol in a 5-ml round-bottomed flask under 1atmosphere of H₂ for 30 minutes. The reaction mixture was filteredthrough celite and evaporated, yielding 78 mg of oil. Purification bypreparative thin layer chromatography (0.25 mm, 20×20 cm; Eluent=1:6 15%NH₃ in MeOH, CH₂Cl₂), yielded 14 mg (16%) of pure 12 (R_(f)=0.5) ¹HNMR(300 MHz, CDCl₃) d 3.89 (br, 2H, NH and OH), 3.82 (d J=10.6 Hz, 1/2CH₂OH), 3.38 (d, J=10.6 Hz, 1/2 CH₂OH), 1.7-1.5 (m, 7H, 3×CH ₂+CH), 1.41(s, 3H, CH₃), 1.37 (s, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃) d 66.8, 64.0,63.8, 45.5, 40.0, 39.1, 39.07, 20.6, 17.8

EXAMPLE 5 Preparation of1,4-Dimethyl-2-exo-carboxymethyl-7-azabicyclo[2.2.1]heptane (13)

The corresponding 2,3-η2-osmium complex 18 was protonated anddecomplexed with Ce(IV) as described for 8. The acetonitrile wasevaporated and the unstable, protonated 7-azanorbornene hydrogenated inmethanol as described for 12. Compound 13 was obtained as an oilfollowing an aqueous workup (e.g., see procedure for 8) and preparativethin layer chromatography purification. ¹H NMR(300 MHz, CDCl₃) d 3.60(s, 3H, CH₃O), 2.63 (dd, J=8.1, 5.1 Hz, 1H, H2), 2.49 (br s, 1H, NH),1.82 (dd, J=12.2, 8.1 Hz, 1H, H3_(endo)), 1.75-1.2 (m, overlap, 5H),1.32 (s, CH₃), 1.2 (s, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃) d 176.5 (CO),67.7, 63.4, 53.0, 51.3, 44.0, 38.3, 36.7, 20.5, 18.3.

EXAMPLE 6 Preparation of1,4-Dimethyl-2-endo-(3′-pyridyl)-3-exo-carboxymethyl-7-azabicyclo[2.2.1]heptane(14a) and its exo-pyridyl-endo-carboxyl isomer (14b)

These isomers were obtained as an inseparable 94:6 mixture from thecorresponding mixture of osmium complexes following the procedure for13. For 14a, ¹H NMR(300 MHz, CDCl₃) d 8.45 (m, 2H, H2′ and H6′ overlap),7.49 (dt, J=7.8, 1.5 Hz, 1H, H4′), 7.23 (dd, J=7.8, 4.8 Hz, 1H, H5′),3.64 (s, 3H, CH₃O), 3.29 (dd, J=5.9, 2.1 Hz, 1H, H2), 2.95 (d, J=5.9 Hz,1H, H3), 2.62 (br s, 1H, NH), 1.85-1.6 (m, 2H, CH₂′s), 1.5 (m, 1H), 1.35(m, 1H), 1.29 (s, 3H, CH₃), 1.26 (s, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃) d175.7 (CO), 149.8 (CH), 148.2 (CH), 135.3 (CH), 134.1 (C), 123.1 (CH),67.6 (2×C overlap), 58.7 (CH), 58.3 (CH), 51.7 (CH₃O), 38.6 (CH₂), 30.3(CH₂), 19.3 (CH₃), 18.7 (CH₃). Diagnostic features of 14b: d 3.36 (d,J=6 Hz, H2), 2.8 (dd, J=6, 2 Hz, H3)

EXAMPLE 7 Preparation of 1,4-Dimethyl-2-endo-(3′-pyridyl)-3-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane (15)

Compound 14 was reduced with lithium aluminum hydride in ether, yieldinga clear resin after an aqueous workup. Diagnostic ¹H NMR resonances:3.87 (dd, J=10.6, 2.8 Hz, 1H, 1/2 CH₂OH), 3.46 (dd, J=10.6, 3.0 Hz, 1H,1/2 CH2OH), 3.16 (dd, J=5.0, 1.9 Hz, 1H, H2), 1.5 (s, 3H, CH₃), 1.25 (s,3H, CH₃)

EXAMPLE 8 Preparation of1,4-Dimethyl-2-endo-(3′-pyridyl)-3-exo-phenylsulfonyl-7-azabicyclo[2.2.1]heptane(16a) and its exo-pyridyl, endo-phenylsulfonyl isomer (16b)

The procedure for compounds 13 and 14 was followed yielding a mixture ofisomeric 7-azanorbornanes. Diagnostic ¹H NMR peaks for major isomer: 3.6(d, J=7 Hz, 1H, CH_(endo)), 2.95 (dd, J=7, 1.5 Hz, 1H, CH_(exo)), 1.85(s, 3H, CH₃), 1.25 (s, 3H, CH₃)

EXAMPLE 9 Preparation of [Os(NH₃)₅(2,3-η²-2,5-dimethylpyrrole)] (OTf)₂(17)

To a solution of [Os(NH₃)₅OTf]OTf₂(1.445 grams, 2.00 mmol) in 1.5 gramsN,N-dimethylacetamide was added 2,5-dimethylpyrrole (1.5 g, 16 mmol) andactivated Mg° (1.0 g, 41 mmol) and the slurry stirred for 45-60 minutes.The slurry was filtered through a medium-porosity frit into 150 mlCH₂Cl₂, giving a light yellow precipitate, which was filtered, washedwith CH₂Cl₂ and ether, then dried. The yield of a light-yellow powderwas 1.23-1.31 g (92-98%).

EXAMPLE 10 Preparation of5,6-exo-η²-Os(NH₃)₅-1,4-dimethyl-2-exo-carbomethoxy-7-azabicyclo-[2.2.1]hept-5-ene)(OTf)₂ (18)

The 2,5-dimethylpyrrole complex (669 mg, 1.0 mmol) was suspended in 2grams methyl acrylate and the slurry stirred for 1 hour. Acetonitrile(c. 1 ml) was added to dissolve the solids and the resulting solutionadded dropwise to 50 ml of ether while stirring. The precipitate wasfiltered, washed with ether and dried, yielding 730 mg (97%) of anoff-white powder. ¹H NMR (300 MHz, CD₃CN) d 3.97 (br s, 3H, trans-NH₃),3.65 (s, 3H, CH₃O), 3.34 (br s, 12H, cis-NH₃), 3.17 (d, J=6.3 Hz, 2H, H5or H6), 3.13 (d, J=6.3 Hz, 1H, H6 or H5), 2.77 (dd, J=8.1, 4.2 Hz, 1H,H2), 2.14 (br s, 1H, NH), 2.05 (dd, J=11.6, 8.1 Hz, 1H, H3_(endo)), 1.63(dd J=11.6, 4.2 Hz, H3_(exo)), 1.39 (s, 3H, CH₃), 1.24 (s, 3H, CH₃); ¹³CNMR (75 MHz, CD₃CN) d 176.4 (CO), 75.7 (C), 71.0 (C), 59.1 (CH), 58.0(CH), 55.3 (CH), 51.6 (OCH₃), 47.1 (CH₂), 18.3 (CH₃), 15.9 (CH₃); Anal.Calcd. for C₁₂H₃₀N₆O₈S₂F₆Os: C, 19.10; H, 4.01; N, 11.14. Found: C,18.57; H, 3.96; N, 11.02.

EXAMPLE 11 Preparation of Pentaammineosmium-Pyrrole Complexes:2,3-η²-[Os(NH₃)₅]-Ligand](OTf)₂, where Ligand is pyrrole or N-methylpyrrole

A mixture of [Os(NH₃)₅OTf](OTf₂) (723 mg, 1.0 mmol),N,N-dimethylacetamide (1 g), DME (3 g), pyrrole or N-methyl pyrrole (1g) and magnesium (0.5 g) was stirred for 1 hour. The solution wasfiltered through a 60-ml medium fritted glass funnel with the aid of10-15 ml of DME, and the filtrate added dropwise to methylene chloride(150 ml). The resulting precipitate was filtered, and washed withportions of methylene chloride (20 ml) and ether (2×20 ml), and driedunder nitrogen. The yield of this reaction is typically 90-95% of ayellow-orange solid containing approximately 8% of a binuclear impurity.

EXAMPLE 12 Preparation of Pentaammineosmium-Cycloadduct Complexes

The pentaammineosmium-pyrrole complex obtained from EXAMPLE 11 wastreated with an excess (3-30 eq) of a dipolarophile in eitheracetonitrile or N,N-dimethylacetamide solution. After 1-10 hours, thesolution was added to ether or methylene chloride with stirring (20 mlof ether per gram of acetonitrile or 75 ml methylene chloride per gramof N,N-dimethylacetamide). The resulting precipitate was worked up asdescribed in Example 11 providing a yield. of 85-95%.

EXAMPLE 13 One-Pot Process for the Synthesis ofPentaammineosmium-Cycloadduct Complexes

A dipolarophile (e.g., methyl acrylate) was added directly to thereaction mixture in the synthesis of the parent pyrrole complex asdescribed in Example 11. After a suitable reaction time (e.g., 1-10hours), the mixture was filtered to remove the magnesium, and thefiltrate was added to 1:1 methylene-chloride/ether (100 ml for everygram of N,N dimethylacetamide used in the synthesis) with stirring. Thesolid was isolated as described in EXAMPLE 11 yielding the cycloadductcomplex as mono-N,N-dimethylacetamide solvate in −95% yield.

EXAMPLE 14 One-Pot Process for the Synthesis of 7-Azanorbornanes fromthe Pentaammineosmium-Cycloadduct Complex

The cycloadduct complex (1.0 mmol) prepared in Example 13 was dissolvedin acetonitrile (4 g), protonated with triflic acid (3-5 eq), andtreated with DDQ (1 eq). The dark solution was transferred to a 50-mlround-bottomed flask with the aid of an additional 20 ml ofacetonitrile, treated with 10% palladium-on-carbon (approximately 0.5 g,40 mole %), and hydrogenated under 1 atm H₂ (balloon) for a suitableperiod of time (2-20 hours) (The pyrrole-derived complexes, lacking asubstituent on nitrogen, underwent reductive amination to N-ethylderivatives in acetonitrile. In these cases the solvent was evaporatedand the reduction carried out in methanol). Workup A: The reactionmixture was filtered through celite to remove the Pd/C, the cake washedwith acetonitrile (or methanol), and the filtrate evaporated. Theresidue was dissolved in water (approximately 10-15 ml), transferred toa separatory funnel, rendered basic with 10% aqueous Na₂CO₃ (20 ml) andextracted with methylene chloride (3×40 ml). The extract was dried overMgSO₄ and evaporated, yielding the crude 7-azanorbornanes. Workup B: Thehydrogenation reaction mixture was treated with 1 ml NH₄OH, diluted withan equal volume of methylene chloride (about 30 ml), then filtereddirectly through 20 cc of silica gel in a 30-ml medium fritted glassfunnel. The flask and silica were washed with an additional 2×30 ml of1:1 methylene chloride/acetonitrile (or methanol) containing ˜3-5%NH₄OH, and the combined eluent evaporated, yielding the crude7-azanorbornanes.

EXAMPLE 15 Preparation of2-Carbomethoxy-7-methyl-7-azabicyclo[2.2.1]heptanes

These compounds, obtained as a 1:1 mixture of isomers, were prepared in66% overall yield from N-methyl pyrrole and methyl acrylate using themethod set forth in Examples 13 and 14 (workup B). The isomers wereseparated by preparative thin layer chromatography using 1:1:5HMDS/Methanol/methylene chloride: Exo isomer (1): R_(f)32 0.76; ¹H NMR(CDCl₃) δ3.66 (s, 3H, CH₃O), 3.62 (d, J=4.2 Hz, 1H, H4), 3.30 (t, J=4.0Hz, 1H, H4), 2.40 (dd, J=9.6, 5.4 Hz, 1H, H2), 2.21 (s, 3H, CH₃N), 2.18(m, 1H), 1.86 (m, 2H), 1.57 (dd, J=12.6, 9.6 Hz, 1H, H3_(endo)), 1.33(m, 2H); ³C NMR (CDCl₃) δ174.6 (C, CO), 64.2 (CH, C1 or C4), 61.1 (CH,C4 or C1), 51.9 (CH₃, CH₃O), 47.4 (CH, C2), 34.5 (CH₃, CH₃N), 33.3(CH₂), 26.7 (CH₂), 26.2 (CH₂); Endo isomer (2): R_(f)=0.62; ¹H NMR(CDCl₃) δ3.65 (s, 3H, CH₃O), 3.44 (t, J=4.5 Hz, 1H, H1 or H4), 3.21 (t,J=4.5 Hz, 1H, H4 or H1), 3.08 (m, 1H, H2), 2.26 (s, 3H, CH₃N), 1.95 (m,1H), 1.75 (m, overlap, 3H), 1.36 (m, 2H); ¹³C NMR (CDCl₃, 50° C.) δ174.3(C, CO), 64.1 (CH, C1 or C4), 62.1 (CH, C4 or C1), 51.4 (CH₃, CH₃O),45.2 (CH, C2), 34.4 (CH₃, CH₃N), 30.6 (CH₂), 28.0 (CH₂), 24.2 (CH₂). Thepicrate salt (both isomers combined) was crystallized from wet ethanol(m.p. 102-108° C.); Anal. Calcd. for C₁₅H₁₈N₄O₉; C, 45.23; H, 4.55; N,14.07. Found: C, 45.42; H, 4.59; N, 14.10.

EXAMPLE 16 Preparation of 2-Cyano-7-methyl-7-azabicyclo[2.2.1] heptanes

These compounds, obtained as a 1:1 mixture of isomers, were prepared in57% overall yield from N-methyl pyrrole and acrylonitrile using themethod set forth in Examples 13 and 14 (workup B). The isomers wereseparated by preparative thin layer chromatography, using 1:1:8HMDS/methanol/methylene chloride. Exo isomer (3): R_(f)=0.71; ¹H NMR(CDCl₃) δ3.53 (d, J=3.3 Hz, 1H, H1), 3.37 (t, J=3.8 Hz, 1H, H4), 2.44(dd, J=9.3, 5.1 Hz, 1H, H2), 2.36 (s, 3H, CH₃N), 2.1 (m, 1H), 1.83 (m,2H), 1.75 (dd, J=12.6, 9.3 Hz, 1H, H3_(endo)), 1.3 (m, 2H); ¹³C NMR(CDCl₃) δ122.7 (C, CN), 65.5 (CH, C1 or C4), 60.8 (CH, C4 or C1), 35.7(CH₂), 35.3 (CH₃), 31.9 (CH), 27.5 (CH₂), 26.9 (CH₂); Endo isomer (4):R_(f)=0.55; ¹H NMR (CDCl₃) δ3.44 (t, J=4.5 Hz, 1H, H1 or H4), 3.29 (t,J=4.5 Hz, 1H, H4 or H1), 2.92 (dtd [11 line pattern], J=12, ˜4.8, 1.8Hz, 1H, H2), 2.26 (s, m overlap, 4H, CH₃N and H3_(exo)), 2.0-1.8 (m,3H), 1.57 (dd, J=12.3, 5.1 Hz, 1H, H3_(endo)), 1.45 (m, 1H); ¹³C NMR(CDCl₃, 50° C.) δ121.7 (C, CN), 63.8 (CH, C1 or C4), 61.6 (CH, C4 orC1), 34.6 (CH₂), 34.4 (CH₃, CH₃N), 29.2 (CH, C2), 27.9 (CH₂), 24.1(CH₂). The picrate salt (both isomers combined) was crystallized fromethanol (mp 218-224° C.): Anal. Calcd. for C₁₄H₁₅N₅O₇: C, 46.03; H,4.14; N, 19.17. Found: C, 45.85; H, 4.08; N, 18.88.

EXAMPLE 17 Preparation oftrans-2,3-Bis-carbomethoxy-7-azabicyclo[2.2.1]heptane

This compound was prepared in 42% overall yield from pyrrole anddimethyl fumarate using the procedures set forth in Examples 11, 12(using acetonitrile as a solvent), and 14 (hydrogenationsolvent—methanol; reaction time—2 h; workup A). ¹H NMR (CDCl₃) δ3.95 (t,J=4.5 Hz, 1H, H4), 3.84 (d, J=4.8 Hz, 1H, H1), 3.70 (s, 3H, CH₃O), 3.695(s, 3H, CH₃O), 3.22 (td, J=4.8, 1.8 Hz, 1H, H3), 3.03 (d, J=4.8 Hz, 1H,H2), 2.55 (br s, 1H, NH), 0.8-1.3 (overlapping m, 4H); ¹³C NMR (CDCl₃)δ174.8 (C, CO), 172.1 (C, CO), 61.8 (CH, C1 or C4), 59.1 (CH, C4 or C1),52.3 (CH), 52.1 (CH₃, CH₃O), 52.0 (CH₃, CH₃O), 50.1 (CH), 28.7 (CH₂),24.9 (CH₂).

EXAMPLE 18 Preparation ofHexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3(2H)-dione

This compound was obtained as a 4:1 mixture of exo and endo isomers,respectively, in 39% overall yield from pyrrole and N-phenylmaleimideusing the procedures set forth in Examples 11, 12 (using acetonitrile asa solvent), and 14 (hydrogenation solvent—methanol; reaction time—2hours; workup A). The crude material was chromatographed on apreparative thin layer chromatography plate (20×20 cm, 2 mm) using agradient elution of ether containing ˜4% conc. NH₄OH and 5, 10, and 20%methanol. Two bands were extracted with ether-methanol: F1 (R_(f)=0.75,ether containing 3% NH₄OH and 10% methanol). This material wasrecrystallized from ethyl acetate-petroleum ether, yielding colorlesscrystals (mp 206-209° C.); exo isomer. ¹H NMR (CDCl₃) δ7.5-7.3 (m, 5H,Ph), 4.15 (t, J=2 Hz, 2H, H1, H4), 2.86 (s, 2H, H2, H3), 1.7 (m, 4H,2×CH₂), 1.54 (br s, 1H, NH); ¹³C NMR (CDCl₃) δ177.3 (CO), 132.1 (C),129.0 (CH), 128.5 (CH), 126.5 (CH), 59.9 (CH, C1, C4), 49.0 (CH, C2,C3), 29.5 (CH₂). The second fraction (R_(f)=0.21) yielded the endoisomer: ¹H NMR δ7.6-7.2 (m, 5H, Ph), 4.18 (br s, 2H, H1 and H4), 3.64(br s, 1H, NH), 3.41 (br s, 2H, H2 and H3), 1.8-1.6 (m, 4H); ¹³C NMRδ175.9 (C), 132.0 (C), 129.7 (CH), 129.3 (CH), 126.9 (CH), 59.6 (CH),51.5 (CH), 26.5 (CH₂).

EXAMPLE 19 Preparation of8-Ethylhexahydro-2-phenyl-exo-4,7-imino-1H-isoindole-1,3(2H)-dione

This compound was formed when the synthesis ofhexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3(2H-dione was carried outusing acetonitrile in the hydrogenation step of the method set forth inExample 14 (reaction time—18 h, workup A). The crude material waschromatographed on silica gel (3.5×13 cm column). Elution with etheryielded 56 mg (21%) of the title product (R_(f)=0.8; ether containingNH₄OH). Further elution with ether containing 10% methanol and 3% conc.NH₄OH yielded a second fraction containing 69 mg of crudehexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3(2H)-dione (R_(f)=0.2;ether containing NH₄OH). The first fraction was treated withdecolorizing charcoal, filtered, evaporated, and the residuerecrystallized from ethyl acetate/petroleum ether. Yield=21 mg oflustrous colorless crystals mp 126-128° C. ¹H NMR (CDCl₃) δ7.5-7.25 (m,5H, Ph), 3.82 (t, J=2.2 Hz, 2H, H1, H4), 2.80 (s, 2H, H2, H3), 2.37 (q,J=7.2 Hz, 2H, NCH₂), 1.93 (m, 2H, H5_(exo), H6_(exo)), 1.51 (m, 2H,H5_(endo), H6_(endo)), 1.04 (t, J=7.2 Hz, 3H, CH₃); ¹³C NMR (CDCl₃)δ177.8 (CO), 132.4 (C, C1′), 129.1 (CH), 128.5 (CH), 126.7 (CH), 62.6(CH, C1, C4), 49.5 (CH, C2, C3), 40.4 (CH₂N), 25.0 (CH₂), 14.5 (CH₃).

EXAMPLE 20 Preparation ofHexahydro-1-hydroxy-2-phenyl-4,7-imino-1H-isoindole-3(2H)-one

The exo imide formed in Example 18 (25 mg. ˜0.1 mmol) was treated withexcess sodium borohydride (40 mg, ˜1.0 mmol) in 5 ml ethanol and themixture refluxed for 20 minutes. The ethanol was evaporated, the residueacidified with 1 M HCl, and treated with Na₂CO₃ and methylene chloride.Evaporation of the extract yielded 20 mg of crude material. Preparativethin layer chromatography (gradient elution; ether containing 5% NH₄OHand 10-20% methanol) yielded the product (R_(f)=0.25, ether with 3%NH₄OH and 10% methanol), still contaminated with a minor product. ¹H NMR(CDCl₃) δ7.55-7.2 (m, 5H, Ph), 5.22 (s, 1H, NCH(OH)), 3.82 (d, J=2 Hz,1H), 2.60 (d, J=2H, 1H), 2.71 (d, J=10 Hz, 1H), 2.08 (d, J=10 Hz, 1H),1.63-1.3 (m, overlap, 6H, 2×CH₂, NH, OH).

EXAMPLE 21 Preparation ofexo-2-aminomethyl-7-methyl-7-azabicyclo[2.2.1]heptane

The nitrile formed in Example 16 (55 mg, 0.4 mmol) was treated withexcess lithium aluminum hydride (30 mg, 0.79 mmol) in 10 ml ether withstirring. After 5 minutes (a white suspension formed), the reaction wasquenched with methanol (0.1 g), then water (0.1 g), acidified with 1 MHCl, then basified with conc., NH₄OH, and extracted with methylenechloride. Drying and evaporation of the extract yielded thecorresponding primary amine as an oil (17 mg, 30%). ¹H NMR (CDCl₃) δ3.18(t, J=3.9 Hz, 1H, H4), 3.03 (d, J=3.9 Hz, 1H, H1), 2.70 (dd, J=12, 7.8Hz, 1H, 1/2CH₂N), 2.51 (dd, J=12, 6 Hz, 1H, 1/2CH₂N), 2.22 (s, 3H,CH₃N), 1.86 (m, 2H), 1.6-1.2 (m, 7H, CH₂+NH₂ overlap).

EXAMPLE 22 Preparation ofexo-2-(1-Pyrrolylmethyl)-7-methyl-7-azabicyclo[2.2.1]heptane

The primary amine formed in Example 21 (17 mg, 0.121 mmol) was treatedwith 2,5-dimethoxytetrahydrofuran (25 mg, 0.189 mmol) in acetic acid(0.1 g) at 150° C. for 5 minutes in an oil bath. Extraction of thebasified (10% aqueous Na₂CO₃) reaction mixture with methylene chlorideyielded a mixture of products from which was obtained 8 mg (˜30%) ofcrude exo-2-(1-pyrrolylmethyl) product by preparative thin layerchromatography using 1:1:8 hexamethyldisilazane/methanol/methylenechloride. ¹H NMR (CDCl₃) δ6.68 (s, 2H), 6.18 (s, 2H), 3.92 (dd, J=15, 12Hz, 1H, 1/2CH₂N), 3.72 (dd, J=15, 7 Hz, 1H, 1/2CH₂N), 3.22 (m, 1H), 2.96(m, 1H), 2.26 (s, 3H, CH₃N), 1.98 (m, 1H), 1.83 (m, 2H), 1.5-1.22 (m,4H).

EXAMPLE 23 Preparation ofexo-2-Hydroxymethyl-7-methyl-7-azabicyclo[2.2.1]heptane

The aminoester formed in Example 15 (41 mg, 0.243 mmol) was treated withlithium aluminum hydride (10 mg, 0.264 mmol) in 5 ml ether. After 5minutes, the reaction mixture was quenched with methanol, acidified with1 M HCl, basified with conc. NH₄OH, and extracted with methylenechloride. Evaporation of the extract yielded the desired product (11 mg,32%). ¹H NMR (CDCl₃) δ3.80 (dd, J=9, 1 Hz, 1H, 1/2CH₂O), 3.39 (dd, J=9,2 Hz, 1H, 1/2CH₂O), 3.21 (t, J=5 Hz, 1H, H4), 3.19 (d, J=4 Hz, 1H, H1),2.18 (s, 3H, CH₃N), 1.82 (m, 3H), 1.7 (m, 1H), 1.5-1.2 (m, 4H).

EXAMPLE 24 Preparation ofezo-2-benzoyloxymethyl-7-methyl-7-azabicyclo[2.2.1]heptane

The alcohol formed in Example 23 (11 mg, 0.078 mmol) was treated withbenzoic anhydride (34 mg, 0.15 mmol) and DMAP (10 mg) in methylenechloride. The product was purified by preparative thin layerchromatography (20×20 cm×0.25 mm) using 1:3:80 NH₄OH/methanol/ether(R_(f)=0.6). Yield: 10 mg (52%). ¹H NMR (CDCl₃) δ8.05 (d, J=7.2 Hz, 2H,ortho-H), 7.55 (t, J=7.2 Hz, 1H, para-H), 7.44 (t, J=7.2 Hz, 2H,meta-H), 4.18 (m, 2H, CH2O), 3.22 (t, J=3.9 Hz, 1H, H4), 3.18 (d, J=3.6Hz, 1H, H1), 2.25 (s, 3H, CH₃N), 2.05-1.85 (m, overlap, 3H), 1.48 (dd,J=12, 9 Hz, 1H, H3_(endo)), 1.34 (m, 3H).

EXAMPLE 25 Preparation of Norbornane Analog of Epibatidine usingReductive Heck Methodology: exo-2-(3-pyridyl)bicyclo[2.2.1]heptane

This procedure is based on that described by R. Larock et al. (J. Chem.Soc. Chem. Comm. 1989, 1368). A mixture of norbornene (101 mg, 1.07mmol), 3-iodopyridine (205 mg, 1.0 mmol), tetra-n-butylammonium chloride(287 mg. 1.03 mmol), potassium formate (255 mg, 3.03 mmol), andpalladium acetate (28 mg, 0.125 mmol) was stirred in DMF (1.2 g) at roomtemperature for 72 hours. The mixture was diluted with 10 ml of 10%Na₂CO₃ (aq) and 10 ml of ether and the aqueous phase extracted againwith ether. The combined extracts were dried over MgSO₄, filtered andevaporated, and the residue purified by preparative thin layerchromatography (20×20 cm, 2.0 mm, 1:1 petroleum ether/ethyl acetate,R_(f)=0.5), yielding the title product as an oil (73 mg, 42%). ¹H NMR(CDCl₃) δ8.42 (s, 1H, H2′), 8.33 (d, J=4.5 Hz, 1H, H6′), 7.43 (d, J=7.8Hz, 1H, H4′), 7.11 (dd, J=7.8, 4.5 Hz, 1H, H5′), 2.67 (dd, J=8.7, 5.7Hz, 1H, H2), 2.30 (m, 2H, 1H, H1 and H4), 1.8-1.2 (m, overlap, 8H,4×CH₂, ¹³C NMR (CDCl₃) δ149.1 (CH), 146.3 (CH), 142.3 (C), 134.0 (CH),122.9 (CH), 44.7 (CH), 42.5 (CH), 38.7 (CH₂), 36.7 (CH), 35.9 (CH₂),30.3 (CH₂), 28.6 (CH₂).

B. Synthesis of the 7-Azabicyclo[2.2.1]-Heptane or -Heptene Ring SystemUsing Diels-Alder Approach

In an alternative embodiment, as illustrated in FIGS. 2a and 2b, activecompounds, or their precursors, are prepared through the Diels-Alderreaction of an N-(electron withdrawing-substituted)pyrrole with anarylsulfonyl(optionally substituted aryl or heterocyclic)acetylene. Theelectron withdrawing group at the N⁷-position decreases the aromaticityof the pyrrole ring and activates the ring in favor of the cycloadditionreaction.

The product of the reaction between the N-(electronwithdrawing-substituted)pyrrole with the arylsulfonyl(optionallysubstituted aryl or heterocyclic)acetylene is a 7-(electron withdrawingsubstituted)-2-(optionally substituted aryl orheteroaromatic)-3-arylsulfonyl-7-azabicyclo[2.2.1]-hepta-2,5-diene(compounds 23 and 32, FIG. 2). This diene can be derivatized usingconventional methods to a wide variety of 7-azabicyclo[2.2.1]-heptanesand -heptenes. For example, an R³ alkyl or aralkyl group can be added byreacting the saturated bicycloheptane derivative of compound 23 or 32with n-butyl lithium and R³I, followed by treatment with a reducingagent to remove the 3-arylsulfonyl moiety. (Julia, M. and Paris, J-M.,Tetrahedron Letters, 49, 4833 (1973).) R⁵ and R⁶ groups can be added tocompound 24 (FIG. 2) by appropriate and conventional reactions of thedouble bond. (See Advanced Organic Chemistry F. A. Carey and R. J.Sundberg (1990) pp. 167-218 Plenum Publishing Co.) Nonlimiting examplesof addition reactions include hydrogenation, hydroboration,hydrohalogenation, hydroxylation, halohydrination, alkylation, carbeneand dihalo carbene addition and epoxidation followed by ring openingreactions with nucleophiles such as alkoxide, amines, alkylsulfide,halide, and hydroxide.

The reactive chloro in compounds 24 and 25 (FIG. 2) is easily displacedby nucleophiles such as alkoxy, including methoxy, alkylthio, hydroxy,amino, cyano, azide, bromide, iodide, and dimethylamino.

The reaction between the N-(electron withdrawing-substituted)pyrrolewith the arylsulfonyl(optionally substituted aryl orheterocyclic)acetylene is carried out in excess N-(electron withdrawingsubstituted)-pyrrole or in a solvent, for example, toluene,tetrahydrofuran, dimethylformamide, diethoxyethane or other inertsolvents. Any molar ratio of pyrrole to dienophile can be used thatprovides an acceptable yield of product, and typically ranges between0.5:1 to 50:1, preferable (1-5):l.

The reaction is conducted at any temperature that produces the desiredproduct, and typically, between room temperature and 150° C., until thereaction is completed, for typically between 1 hour and 72 hours at 1atm. or elevated pressure in a sealed reactor.

Several methods have been investigated for the removal of the N-electronwithdrawing group, and specifically, the N-carbomethoxy protectinggroup, after synthesis of the desired 7-azabicyclo[2.2.1]-heptane or-heptene framework. Hydrolysis of compound 25 (FIG. 2) with potassiumhydroxide in methanol results in substitution of the moderately reactivechlorine in the pyridine ring by a methoxy group. Treatment of 25 withmethyllithium stopped at the formation of N-acetyl epibatidine(identical with an authentic sample from acetylation of rac-epibatidineas described below), which resisted further cleavage by methyllithiumeven after a prolonged treatment. This is in accordance with the knownstability of N-acetyl epibatidine. Compound 25 is successfully deblockedby treatment with hydrobromic acid in acetic acid for 24 hours at roomtemperature. The products isolated from silica gel chromatography, witha mixed solvent system of ethyl acetate, methylene chloride and ammoniain methanol as the eluent, were rac-epibatidine (19, 25%),rac-endo-epibatidine (19′, 28.4%) and unchanged carbamate (25, 20%).Notably, the recovered starting material is essentially the pure endoisomer of 25, indicating some stereoselectivity in the cleavage of theN-carbomethoxy group with hydrobromic acid. The exo-isomer wasapparently cleaved at a higher rate than the endo-isomer, presumablyinfluenced by the proximity of the pyridyl group and the carbamategroup. The rac-epibatidine thus obtained, m.p. 50-51°, is very pure, asevidenced by its spectral data.

i). N-(Electron Withdrawing-substituted)pyrrole

Many substituted pyrroles are known and are easily converted toN-(electron withdrawing-substituted)-pyrroles for use in the Diels-Alderprocess to prepare 7-azabicyclo[2.2.1]heptanes and -heptenes. Forexample, 3-(thioalkyl)pyrrole, including 3-(SCH₃)pyrrole;2,5-dialkylpyrrole, including 2,5-dimethylpyrrole;3,4-dihaloalkylpyrrole, including 3,4-bis(trifluoromethyl)pyrrole,2-alkylpyrrole, including 2-methylpyrrole; 2-alkoxyalkylpyrrole,including 2-methoxymethylpyrrole; 2-alkylthioalkylpyrrole, including2-methylthiomethylpyrrole; 2-dialkylaminoalkylpyrrole, including2-dimethylaminomethylpyrrole; alkyl pyrrole 2-acetate, includingdimethylaminomethylpyrrole; alkyl pyrrole 2-acetate, including methylpyrrole 2-acetate; 2-alkoxyalkoxyalkylpyrrole, including2-methoxymethoxyethylpyrrole; 3-aryloxyalkylpyrrole, including3-benzyloxymethylpyrrole; 2-alkoxypyrrole, including 2-methoxypyrrole;3-alkoxypyrrole, including 3-methoxypyrrole; 3-aryloxypyrrole, including3-benzyloxypyrrole; 3,4-dialkylpyrrole, and 3-alkylpyrrole, including3-methylpyrrole and 3,4-dimethylpyrrole; 1,6 and 4,5-alkylidene pyrrole,including 4,5,6,7-tetrahydroindole and2-methyl-4,5,6,7-tetrahydroindole.

The N-substituent on the pyrrole ring is any moiety that is electronwithdrawing and that activates the ring toward cycloaddition with adienophile. The N-substituent is preferably carbomethoxy, however, otherelectron withdrawing moieties, including carbobenzyloxy,tert-butoxycarbonyl and optically active alkoxycarbonyl, including (+)and (−)-menthyloxycarbonyl can also be used.

ii). Arylsulfonyl(Optionally Substituted Aryl orHeteroaromatic)acetylene

In this process, a compound of the formula aryl-SO₂C≡C-(optionallysubstituted aryl or heteroaromatic) is reacted with the N-(electronwithdrawing-substituted)pyrrole or its derivative.

The arylsulfonyl-(optionally substituted aryl orheteroaromatic)-acetylene can be prepared by methods known to those ofskill in the art. In one embodiment, described in detail in the Example26 below, the compound is prepared by reacting the lithium salt ofmethyl(aryl)sulfone with the desired optionally substituted aryl orheteroaromatic acid chloride to produce a 1-(aryl orheteroaromatic)-2-arylsulfonylethanone, that is converted to thecorresponding acetylene via an enolphosphate intermediate as describedin Example 27 below. Any optionally substituted aryl or heteroaromaticacid chloride can be used, including without limitation, the acidchloride of nicotinic acid, isonicotinic acid, 5-chloronicotinic acid,6-methylnicotinic acid, 6-methoxynicotinic acid, 6-phenylnicotinic acid,6-methylthionicotinic acid, 2-chloropyridine-4-carboxylic acid,2,6-dimethylpyridine-4-carboxylic acid,1-methyl-2(1H)-pyridone-3-carboxylic acid, 6-methylthionicotinic acid,3-quinolinic acid, 4-quinolinic acid, 7-chloro-3-quinolinic acid,6-methoxy-3-quinolinic acid, isoquinoline-4-carboxylic acid,5-chloro-thiophene-2-carboxylic acid, pyrimidine-5-carboxylic acid,5-methoxyindole-3-carboxylic acid, 1,2,5-thiadiazole-2-carboxylic acid,thiazole-5-carboxylic acid, 2-chloro-thiazole-5-carboxylic acid, and5-chloropyridazine-2-carboxylic acid. Substituents that can bepositioned on the aromatic or heteroaromatic group include, but are notlimited to, alkyl, halo, aryl, alkoxy, dialkylamino, alkylthio, hydroxy,hydroxyalkyl, and C(O)(alkyl or aryl).

The aryl group attached to the sulfone can be any group thatsufficiently activates the acetylenic group to act as a dienophiletoward the activated pyrrole and which does not interfere with thecycloaddition reaction. Nonlimiting examples are phenyl, p-alkylphenyl,including p-methylphenyl; halophenyl, and including p-chlorophenyl,p-fluorophenyl, and p-nitrophenyl. Fluoroalkanesulfonyl, includingCF₃SO₂ and C₄F₉SO₂, can also be used to activate an aryl- orheteroarylacetylene.

Methods to prepare a wide variety of arylsulfonyl-(aryl orheteroaromatic)-acetylenes are described in Bhattacharya, S. N., et al,Organomet. Chem. Synth. 1, 145 (1970), and the reaction of an aryl orheteroaromatic trimethylsilyl acetylene (Sakamoto, T., et al.,Synthesis, 312 (1983)) with tosyl chloride in the presence of a Lewisacid catalyst such as aluminum trichloride.

The process for preparing active compounds through the Diels-Alderreaction of an N-(electron withdrawing-substituted)pyrrole with anarylsulfonyl(optionally substituted aryl or heterocyclic)acetylene isset out in detail in the working examples below. These examples aremerely illustrative, and not intended to limit the scope of the processor the compounds that can be made according to the process. As discussedabove, this is a general method that can be combined with conventionalsynthetic techniques to provide a wide variety of products, all of whichare considered to fall within the scope of the invention. The compoundsare numbered as illustrated in FIG. 2.

EXAMPLE 26 Preparation of1-(2-chloro-5-pyridyl)-2-phenylsulfonylethanone (9)

To a cold solution (−30° C.) of 20 g methyl phenyl sulfone in 400 mldried tetrahydrofuran was added 128 ml 2.5M n-butyllithium (2.4 eq)slowly. The resulting solution was stirred at −30° C. for 30 minutes. Asolution of 26 g 6-chloronicotinyl chloride in 100 ml tetrahydrofuranwas then added during a 20 minute period. After stirring at the sametemperature for 30 minutes, the mixture was quenched by addition of sat.ammonium chloride (ca. 100 ml). The organic layer was separated and theaqueous layer extracted with chloroform three times. The combinedorganic layer was washed with sat. brine and dried over magnesiumsulfate. After removal of solvent, the brown solid was triturated withmethanol (150 ml) to give 7.06 g of a slightly yellow solid. Anothercrop of the product (11.75 g) was obtained from the mother liqueur bychromatography on a short silica gel column using 50% ethyl acetate inpetroleum ether as the eluent. The total yield is 18.81 g (49.7%). m.p.152-3° C. MS(CI) m/z 296, 298(M+1).

In a similar manner, when the acid chlorides of nicotinic acid,isonicotinic acid, 5-chloronicotinic acid, 6-methylnicotinic acid,6-methoxynicotinic acid, 6-phenylnicotinic acid, 6-methylthionicotinicacid, 2-chloropyridine-4-carboxylic acid,2,6-dimethylpyridine-4-carboxylic acid,1-methyl-2(1H)pyridone-3-carboxylic acid, 6-methylthionicotinic acid,3-quinolinic acid, 4-quinolinic acid, 7-chloro-3-quinolinic acid,6-methoxy-3-quinolinic acid, isoquinoline-4-carboxylic acid,5-chloro-thiophene-2-carboxylic acid, pyrimidine-5-carboxylic acid,5-methoxyindole-3-carboxylic acid, 1,2,4-thiadiazole-2-carboxylic acid,thiazole-5-carboxylic acid, 2-chloro-thiazole-5-carboxylic acid,5-chloropyridazine-2-carboxylic acid are used in place of6-chloronicotinyl chloride in the condensation reaction, thecorresponding ketosulfones are obtained.

EXAMPLE 27 Preparation of 2-chloro-5-pyridyl phenylsulfonyl acetylene(22)

A solution of 3.34 g (11.3 mmol) of 20 in 100 ml dried tetrahydrofuranwas added to a suspension of 840 mg 60% sodium hydride (washed withethyl ether) in 100 ml tetrahydrofuran. After stirring 10 minutes, 1.88ml (11.3 mmol) diethyl chlorophosphate was added in one portion. Themixture was stirred at room temperature overnight, then cooled to −78°C., and 1.35 g potassium t-butoxide is added in portions. The brownsolution was stirred at −78° C. for another 10 minutes and allowed towarm to ca. −30° C. Water was added and the aqueous layer extracted withmethylene chloride. After drying and evaporation in vacuo, the residuewas purified on a silica gel column, and eluted with 25% ethyl acetatein petroleum ether. The white solid (1.2 g) obtained after evaporationof solvent has a m.p. 140-141° C. MS(CI) m/z 278, 280(M+1), yield 38%.

In a similar manner, when other heterocyclic ketosulfones described inExample 26 are used in place of compound 20, the correspondingacetylenes are obtained.

EXAMPLE 28 Preparation of N-carbomethoxy pyrrole (21)

Potassium (5.85 g, 0.15 mol) was added to a solution of 10 ml pyrrole(0.145 mol) in 80 ml hot cyclohexane in several portions. The mixturewas refluxed for 1 hour. To this cold solution was added 15 g (0.16 mol)methyl chloroformate slowly. After addition, the mixture was stirred atroom temperature for 30 minutes. During this period, 2.5 ml dimethylsulfoxide was added for catalysis. After quenching with ice-water, theorganic layer was separated and the aqueous layer extracted with ether.The combined organic layer was washed with 10% sodium bicarbonate, sat.sodium chloride and dried over magnesium sulfate. Removal of solventyielded 17.4 g of a liquid. Bulb to bulb distillation gives 16.5 gN-carbomethoxy pyrrole 21 as a colorless liquid, yield 91%. The productrequires storage at −20° C.

In a similar manner, the N-carbomethoxy, N-carbobenzyloxy andN-tert-butoxycarbonyl derivatives of 2,5-dimethylpyrrole,3,4-bis(trifluoromethyl)pyrrole, 2-methylpyrrole,2-methoxymethylpyrrole, 2-methylthiomethylpyrrole,2-dimethylaminomethylpyrrole, methyl pyrrole-2-acetate,2-methoxymethoxyethylpyrrole, 3-benzyloxymethylpyrrole,2-methoxypyrrole, 3-methoxypyrrole and 3-benzyloxypyrrole are prepared.

EXAMPLE 29 Preparation of7-carbomethoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-aza-bicyclo[2.2.1]-2,5-diene(23)

2-Chloro-5-pyridyl phenylsulfonyl acetylene 22 (1.12 g, 40.3 mmol) wasdissolved in 8.0 g N-carbomethoxy pyrrole 21. The mixture was stirred ina covered flask at 80-85° C. for 24 hours. After evaporation in vacuo torecover N-carbomethoxy pyrrole, the residue was chromatographed on asilica gel column using 25% to 50% ethyl acetate in petroleum ether aseluent to recover 0.2 g of the acetylene 22 and obtain 1.21 g of aslightly dark product. The crude product was triturated with methanol toyield 0.94 g (58% or 70% according to recovered starting material) of awhite solid. m.p. 101° C. MS(CI) m/z 403, 405 (M+1). When thearylsulfonyl acetylene derivatives described in Example 27 are used inplace of compound 22 in this experiment, the corresponding Diels-Alderadducts are obtained.

EXAMPLE 30 Preparation of7-carbomethoxy-5-(2-chloro-5-aza-bicyclo[2.2.1]hept-2-ene (24)

Compound 23 (0.726 g, 1.9 mmol) was dissolved in 50 ml anhydrousmethanol and 7 ml dried tetrahydrofuran containing 1.0 g (8.0 mmol) ofsodium dihydrophosphate. To this mixture was added 3.0 g 6% sodiumamalgam in two portions at −20° C. under nitrogen. The stirred mixturewas allowed to warm spontaneously to room temperature during a 2 hourperiod and stirred at room temperature for another hour. The upper layerwas decanted and the residue washed with methanol. Water and 10% HClwere added to the combined methanolic extracts to bring the pH to 6 andmost of the methanol removed in vacuo. The mixture was then extractedwith methylene chloride. The combined organic layer was washed with sat.brine and dried over magnesium sulfate. After removal of solvent, theresidue was purified on a silica gel column using 33% ethyl acetate inpetroleum ether as the eluent to yield 215.3 mg (42.9%) of a colorlessoil. ¹H-NMR shows that it is a (1:2) mixture of exo and endo isomers. MS(CI) m/z 265, 267 (M+1). ¹HNMR 6.01-6.53(2H, H_(5,6)), 4.61-4.91(2H,H_(1,4)). When other Diels-Alder adducts described in Example 29 aretreated with sodium amalgam in a similar manner, the correspondingsubstituted 7-aza-bicyclo[2.2.1]hept-2-enes are obtained.

EXAMPLE 31 Preparation of7-carbomethoxy-2-(2-chloro-5-pyridyl)-7-aza-bicyclo[2.2.1]heptane (25)

Compound 24 (178.4 mg, 0.674 mmol) (mixture of isomers) was dissolved in10 ml methanol containing 5 mg 10% Pd—C. The mixture was hydrogenatedunder 1 atm. of hydrogen. After 18 ml of hydrogen was absorbed (5minutes), the catalyst was removed by filtration and methanol removed invacuo to give 165 mg (92%) of colorless oil. ¹H-NMR indicates that it isa (1:2) mixture of exo and endo isomers. MS(CI) m/z 267, 269 (M+1).¹H-NMR 4.21-4.44(2H, H_(1,4)). In a similar manner, other substituted7-aza-bicyclo[2.2.1]hept-2-enes described in Example 30 are hydrogenatedto the corresponding substituted 7-aza-bicyclo[2.2.1]heptane analogs.

EXAMPLE 32 Preparation of racemic epibatidine (19) and endo-epibatidine(19′)

Compound 25 (90 mg, 0.338 mmol) was dissolved in 2.5 ml hydrobromic acid(33% in acetic acid). The mixture was stirred at room temperature for 20hours. After evaporation of the mixture in vacuo the residue wasdissolved in water and extracted with ethyl ether to recover thestarting material (26 mg). The aqueous layer was neutralized withpotassium hydroxide to pH 11 and extracted with methylene chloride. Thecombined organic layer was washed with saturated brine and dried overmagnesium sulfate. After removal of the solvent, the 56 mg residue waschromatographed on silica gel column using ethyl acetate, methylenechloride and sat. ammonia methanol (2:1:0.03) to give 18 mg (25%) ofepibatidine (19) m.p. 50-51° and 20 mg (28.4%) of endo-epibatidine(19′). The spectral data for these compounds is provided in Table 3.

TABLE 3 Spectra data for epibatidine (19) and endo-epibatidine (19′)epibatidine (19) endo-epibatidine (191) MS(CI)m/z 209, 211 (M + 1) 209,211 (M + 1) H¹-NMR H_(1.4), 3.80(t, 3.9 Hz), 3.76(q, 4.8 Hz) 3.56(br.s)H_(3e) 1.90(dd, 12.0, 2.12(tdd, 12.3, 4.8, 9.0 Hz) 3.3 Hz)

The N-acetyl derivatives of epibatidine can be prepared from epibatidineand acetic anhydride in the presence of triethylamine. Likewise, otherN-substituted 7-azabicyclo[2.2.1]heptanes described in Example 31 aredeprotected to the corresponding free amine. The amines are readilyacylated to the amide, alkylated to the tertiary amine and quaternaryammonium derivatives by using conventional methods. The amines also formstable and water-soluble salts with organic and inorganic acids aspreferred in the pharmaceutical formulation.

EXAMPLE 33 Preparation of7-carbomethoxy-2-(2-methoxypyridyl)-7-aza-bicyclo[2.2.1]heptane (29)

7-Carbomethoxy-2-(2-chloro-5-pyridyl)-7-aza-bicyclo[2.2.1]heptane 25 (20mg, 0.076 mmol) was dissolved in 1.0 ml methanol containing 12.8 mg (0.2mmol) potassium hydroxide. The mixture was refluxed for one hour, thenconcentrated and partitioned between ethyl ether and water. The aqueouslayer was extracted with ether again and the combined organic layer waswashed with sat. sodium bicarbonate, and dried over magnesium sulfate.Removal of solvent yielded a 10 mg residue. H¹-NMR shows it is a 1:2mixture of exo and endo isomers of the title compound. H¹-NMR 3.92,3.90(2s, Py-OCH₃), 3.71, 3.66(2s, NCOOCH₃).

EXAMPLE 34 Preparation of deschloro analogues of epibatidine (30)

N-carbomethoxy-5-(2-chloro-5-pyridyl)-7-aza-bicyclo[2.2.1]hept-2-ene 25(16 mg) was dissolved in 3 ml methanol containing 7 mg 10% palladium oncarbon. The mixture was hydrogenated under a slightly elevated pressureof hydrogen for one hour. After removal of catalyst and solvent, theresidue was partitioned between ether and aqueous sodium bicarbonate.The aqueous layer was extracted with ether and the combined organiclayer was dried over magnesium sulfate. Removal of solvent gave 10 mg of7-carbomethoxy-2-(3-pyridyl)-7-azanorbornane (12). MS (CI) m/z 233(M+1), H¹-NMR 3.72, 3.66 (2s, N-COOCH₃).

EXAMPLE 35 Preparation of 5,6-dehydro analogs of epibatidine

When the N-acylated 7-aza-bicyclo[2.2.1]hept-5-ene derivatives preparedin Example 30 are acid hydrolyzed under conditions similar to thatdescribed in Example 32, the corresponding 5,6-dehydro analogs ofepibatidine (19) and its endo-isomer (19′) are obtained.

EXAMPLE 36 Preparation of1,4-dimethyl-2-(6-chloro-3-pyridyl)-3-phenylsulfonyl-7-carbomethoxy-7-aza-bicyclo[2.2.1]hept-2,5-diene

A mixture of 0.14 g (0.5 mmol) 2-chloro-5-pyridyl phenylsulfonylacetylene(22) and 0.7 g 2,5-dimethyl-N-carbomethoxypyrrole (31) washeated and maintained at 85° C. for 48 hour. The excess pyrrole (31) wasremoved in vacuo and the dark residue chromatographed on silica gelusing 25%-33% ethyl acetate in petroleum ether as eluent, yielding 76 mg(35%) of the title compound. MS(CI) m/z 431, 433 (M+1). H¹-NMR 6.79,6.55 (AB J=5.4 Hz, H_(5,6)), 3.52(s, 3H, N-COOCH₃), 1.96, 1.68(2s, 6H,2CH₃).

EXAMPLE 37 Preparation of benzoyl phenylsulfonyl methane (32)

A procedure similar to the preparation of compound 20 was used. Theproduct was obtained in 60% yield as a white crystal (crystallized fromcarbon tetrachloride). m.p. 91-93° C. (lit, m.p. 93-94° C.).

When the acid chloride of 4-chlorobenzoic acid, 3-methoxybenzoic acid,3,4-methylenedioxybenzoic acid, 3,4,5-trimethoxybenzoic acid,3-trifluoromethylbenzoic acid, 3-dimethylaminobenzoic acid,4-methylthiobenzoic acid, 4-methylsulfinylbenzoic acid,4-methylsulfonylbenzoic acid, 3,5-difluorobenzoic acid, 2-naphthoicacid, 4-dimethylamino-2-naphthoic acid, 6-methoxy-2-naphthoic acid,2-phenylpropionic acid and 2-(3,4-methylenedioxyphenyl) propionic acidare used in place of benzoyl chloride above, the correspondingsubstituted ketosulfones are prepared.

EXAMPLE 38 Preparation of phenyl phenylsulfonyl acetylene (34)

A procedure similar to the preparation of compound 22 was used.Chromatography of the crude product on silica gel using 5% ethyl acetatein petroleum ether as the eluent yielded 20% of the acetylene 34 as asolid.

Using a similar procedure, the other ketosulfones described in Example37 are converted to the corresponding substituted aryl and aralkylacetylenic derivatives.

EXAMPLE 39 Preparation of7-carbomethoxy-2-phenyl-3-phenylsulfonyl-7-azanorborna -2,5-diene (35)

Phenyl phenylsulfonyl acetylene 34 (84.3 mg, 0.35 mmol) was mixed with0.42 g of N-carbomethoxy pyrrole (21). The mixture was heated to andmaintained at 85° C. for 48 hours. After removal of the excess pyrrole,the residue was chromatographed on silica gel column and eluted with25-33% ethyl acetate in petroleum ether to give 30 mg (23%) of theadduct as a colorless oil. MS(CI) m/z 368(M+1). H¹-NMR 7.05(s, 2H,H_(5,6)), 5.51, 5.48(2s, 2H, H_(1,4)), 3.5(br.s. 3H, N-COOCH₃).

Using a similar procedure, cycloadditions of substituted pyrrolesdescribed in Example 28 and substituted acetylenic derivatives preparedin Example 38 give the corresponding 7-aza-bicyclo[2.2.1]hepta-2,5-dieneadducts.

EXAMPLE 40 Preparation of 2-phenyl-7-aza-bicyclo [2.2.1]heptane (36)

The bicyclic adduct 35 was reductively desulfonated, hydrogenated andacid hydrolyzed as described in Examples 30, 31 and 32 to yield 36.Similarly, the other bicyclic adducts in Example 39 are converted to thecorresponding 2-substituted aryl-7-aza-bicyclo[2.2.1]heptanes.

EXAMPLE 41 Preparation of 2-phenyl-7-aza-bicyclo[2.2.1]hept-5-ene (37)

The bicyclic adduct 35 is reductively desulfonated and acid hydrolyzedas described in Examples 30 and 32 to yield 37. Similarly, the otherbicyclic adducts in Example 39 are converted to the corresponding2-substituted aryl-7-aza-bicyclo[2.2.1]hept-5-enes.

EXAMPLE 42 Preparation of 5 and/or 6 substituted 2-aryl (orheteroaryl)-7-aza-norbornanes from the corresponding 7-N-acyl or7-aza-2-aryl (or heteroaryl)-norborn-5-enes

The 5 and/or 6-substituents are introduced by functioning the 5,6-doublebond through conventional reactions, e.g., additions, hydroboration,epoxidation followed by ring opening with nucleophiles (alkoxide, amine,azide, alkylsulfide, halide, hydroxide, etc.).

EXAMPLE 43 Preparation of3-methyl-7-aza-2-exo-(2-chloro-5-pyridyl)bicyclo[2.2.1]heptane (38)

7-Carbomethoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hept-2,5-diene(23) is hydrogenated in methanol containing 10% Pd—C until both doublebonds are saturated. The product,7-carbomethoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-aza-bicyclo[2.2.1]heptane39, is dissolved in dry tetrahydrofuran and treated with n-butyl lithium(1.1 eq) at −30 to 0° C., followed by methyl iodide (1-1 eq) intetrahydrofuran. The reaction mixture is then stirred at roomtemperature and poured into iced water. The product is extracted withether and washed with water. After drying and evaporation of the ethersolution, the crude product is chromatographed on a silica gel column,using a mixture of petroleum ether and ethyl acetate (3:1 by volume) toyield stereoisomers of7-carbomethoxy-2-(2-chloro-5-pyridyl)-3-methyl-3-phenylsulfonyl-7-aza-bicyclo[2.2.1]heptane(40).The alkylation products are each treated with sodium amalgam as inExample 30 to remove the phenylsulfonyl group, followed by acid cleavageof the 7-carbomethoxy group as in Example 32 to yield isomeric 3-methylanalogs of compound 8 and 8′.

Similarly, when methyl iodide is replaced by ethyl bromide, allylbromide, benzyl chloride, methoxymethyl chloride and methoxyethylmethanesulfonate, and corresponding 3-ethyl, 3-allyl, 3-benzyl,3-methoxymethyl and 3-methoxyethyl derivatives are obtained.

Other 2-aryl or 2-heteroaryl derivatives of7-N-acyl-7-aza-3-phenylsulfonyl-bicyclo[2.2.1]hepta-2,5-diene describedin Example 29 are likewise hydrogenated, converted to the sulfonylcarbanion, alkylated, desulfonated and deacylated to give thecorresponding 3-alkyl or aralkyl analogs.

EXAMPLE 44 Preparation of7-methyl-7-aza-2-exo-(2-chloro-5-pyridyl)bicyclo[2.2.1]heptane (41)

Epibatidine 19 prepared in Example 32 is alkylated with methyl iodide(1.1 eq) in dry tetrahydrofuran at room temperature, followed by theusual isolation procedure, to give the 7-N-methyl derivative.

Similarly, alkylation with ethyl iodide, isopropyl bromide, allylbromide, cyclopropylmethyl bromide, benzyl chloride, 4-methoxybenzylchloride, 3,4-dimethoxybenzyl chloride, phenethyl bromide, propargylbromide, hydroxyethyl chloride and methoxyethyl iodide yield thecorresponding 7-N-alkylated derivatives.

Other substituted 7-aza-bicyclo[2.2.1]heptane analogs described in theexamples above are alkylated to their 7-N-alkyl is derivatives in thesame manner.

The N-acetyl derivative of epibatidine in Example 7 is reduced to theN-ethyl derivative by the treatment of lithium aluminum hydride in drytetrahydrofuran at room temperature. Similarly, the 7-N-propionyl,N-benzoyl, N-phenylacetyl and N-2-furoyl derivative of epibatidine arereduced to the corresponding 7-propyl, 7-benzyl, 7-phenethyl and7-(2-furfuryl) derivatives.

EXAMPLE 45 Resolution of Racemic Compounds

The substituted 7-aza-bicyclo[2.2.1]heptane derivatives are resolved totheir optical isomers by conventional methods including chromatographyon a chiral column, fractional crystallization of diastereomeric saltsof chiral acids and separation of the chiral ester or amide derivativesfollowed by regeneration of the optically pure enantiomers. (See OpticalResolution Procedures for Chemical Compounds, Vol. 1, Amines. by P.Newman, 1980 Optical Resolution Information Center, N.Y. 10471.)

EXAMPLE 46 Resolution of Racemic Epibatidine (19)

To a solution of racemic epibatidine 19 and triethylamine (1.1 eq) inmethylene chloride is added (−)-menthyl chloroformate (1.1 eq). Thereaction mixture is stirred at room temperature for 6 hours, washed withiced water and dried over magnesium sulfate. After evaporation ofsolvent, the residue is chromatographed on a silica gel column, using amixture of petroleum ether and ethyl acetate (5:1 by volume) to yield amixture of two diastereoisomers of 7-N-(−)-menthyloxycarbonylderivatives of d- and l-epibatidine. Separation of the diastereoisomersby HPLC on a chiral column and treatment of each isomer with HBr/AcOH asin Example 32 yields the corresponding d and 1-epibatidine.

EXAMPLE 47 Preparation of Optical Isomers of Substituted7-aza-bicyclo[2.2.1]heptane Derivatives from Chiral Intermediates

N-carbo-(−)-menthyloxy pyrrole is prepared from pyrrole and (−)-menthylchloroformate by the method described above. The chiral pyrrole istreated with the sulfonyl acetylene 22 or 34 as in Example 29 to give adiastereoisomeric mixture of the chiral cycloadduct7-aza-bicyclo[2.2.1]hepta-2,5-diene derivative. After treatment withsodium amalgam as in Example 30, the diastereoisomeric mixture of2-exo-aryl-7-aza-bicyclo[2.2.1]hepta-5-ene derivatives is obtained.These diastereomers are separated by chromatography to give the d and lenantiomers. The optically active intermediates are each reduced andtreated with HBr/AcOH to yield optically active epibatidine enantiomers.Similarly, other substituted 7-aza-bicyclo[2,2,1]heptane analogs areprepared from the corresponding chiral pyrroles and chiral cycloadducts.

EXAMPLE 48 Preparation of benzo[5a,6,a]epibatidine (39)

Scheme 4 illustrates the preparation of compound 39.

a) Preparation of N-methanesulfonyl isoindole (40)

Sodium hydride (0.88 g) was suspended in 3 ml dimethyl formamide. Tothis stirred solution was added methanesulfonamide (0.95 g, 10 mmol) in5 ml dimethyl formamide dropwise under nitrogen. After stirring at 60°C. for 0.5 hours, a solution of 2.64 g (10 mmol) α,α′-dibromo-o-xylenein 7 ml DMF was added at a rate appropriate to maintain the temperatureat 60-70° C. The mixture was stirred at room temperature for anotherhour, then quenched by pouring into water. The resulting precipitate wascollected and washed with water, petroleum ether and ether successively.Weight 1.57 g (80%). ¹H-NMR δ2.37 (s, 3H, —CH₃), 4.709 (s, 4H, 2CH₂).7.25˜7.35 (m. 4H, ArH).

b) Preparation of2-(6-chloro-3-pyridyl)-3-phenylsulfonyl-1,4-dihydronaphthalene-1,4-imine(41)

Potassium t-butoxide (560 mg, 5.0 mmol) was dissolved in 3 ml DMSO undernitrogen. To this stirred solution was added 197 mg (1.0 mmol)N-methanesulfonyl isoindole in portions. After addition, the mixture wasstirred at room temperature for 1.5 hours and quenched by addition of 3ml water. After extraction with 45 ml ether, the combined organic layerwas washed with saturated brine and dried over magnesium sulfate for 10minutes. After filtration, the filtrate was combined with 83 mg (0.3mmol) 1-(6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene 22. The reactionmixture was stirred at room temperature overnight to evaporate in vacuoand chromatographed on silica gel column. Eluting with a mixed solvent(ethyl acetate, methylene chloride and ammonia in methanol) gave 108 mgblue residue. The color material was removed by washing the acidifiedmaterial. After basification and extraction with ether, 62 mg of purecompound 41 was obtained as a foam. Yield 52%. MS(CI), 395, 397(M+1).′H-NMR (CDCl₃): δ5.242(d, J=1.5 Hz, 1H), 5.362 (d, J=0.9 Hz, 1H). (H₁ orH₄).

c) Preparation of exo and endo-benzo [5a,6a]epibatidine (39)

Compound 41 (54 mg, 0.137 mmol) was dissolved in a mixture of 3 mlmethanol and 1 ml tetrahydrofuran. The solution was cooled to −20° C.and 66 mg 6% sodium amalgam was added. The mixture was stirred for 2hours. The excess reagent was decomposed by water and the liquid layerwas decanted out. After concentration of the liquid in vacuo, theresidue was extracted with methylene chloride (3×5 ml). The combinedorganic layer was washed with saturated brine and dried over magnesiumsulfate. After removal of solvent, the residue was separated onpreparative thin layer chromatography with 33% methylene chloride inethyl acetate to give 5.5 mg exo-benzo [5a,6a]epibatidine and 8.5 mgendo-benzo [5a,6a]epibatidine. Both isomers are an oil. Yields are 15%and 25% respectively. MS(CI), 257, 259(M+1). ¹H-NMR (CDCl₃), (forexoisomer). 2.753 (dd, J=4.8, 8.4 Hz, 1H, H₂), 4.371 (s, 1H, H₁), 4.656(d, J=4 Hz, 1H, H₄).

EXAMPLE 49 Preparation of N-methyl-benzo [5a,6a]epibatidine (42)

Scheme 5 illustrates a method for the production of N-methyl-benzo[5a,6a]epibatidine 42.

a) Preparation of N-methyl isoindole (43)

N-methyl isoindole was prepared according to the method set forth in B.Zeeh and K. H. König, Synthesis 1972, 45.

b) Preparation of2-(6-chloro-3-pyridyl)-3-phenylsulfonyl-1,4-dihydronaphthalene-1,4-imine(44)

N-methyl isoindole (91 mg, 0.7 mmol) was mixed with1-(6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene 22 (139 mg, 0.5 mmol)in ethyl ether. After stirring at room temperature for 1 hour, themixture was concentrated and chromatographed on silica gel column,eluting with ethyl acetate. This gave 204 mg of compound 44 as a clearoil. Yield 100%. MS(CI), 409, 411(M+1). H¹-NMR (CDCl₃). δ2.36 (br, 3H,⁻NCH₃), 4.805 (s, 1H), 4.93 (br.s., 1H), (H₁, or H₄).

c) Preparation of N-methyl-benzo [5a,6a]epibatidine (42)

Compound 44 (125 mg, 0.306 mmol) was dissolved in 10 ml methanoltogether with 4 ml tetrahydrofuran. The solution was cooled to −20° C.and 216 mg sodium dihydrophosphate was added to the solution followed by1.0 g 6% sodium amalgam. The mixture was then stirred at roomtemperature for 3 hours and quenched with water. The organic layer wasdecanted out and concentrated in vacuo. The residue was extracted withmethylene chloride (2×10 ml). The combined organic layer was washed withsaturated brine and dried over magnesium sulfate. After removal ofsolvent, the residue was chromatographed on silica gel column elutingwith 50% ethyl acetate in petroleum ether. This gave 19 mg (19%)exo-N-methyl-benzo[5a,6a]epibatidine. Further elution with a mixedsolvent (ethyl acetate, methylene chloride and ammonia in methanol)yielded 55 mg (66%) of the endo-isomer. Total yield 85%. MS(CI), 271,273(M+1). H¹-NMR (CDCl₃), (for exoisomer): 2.679 (dd, J=4.5, 8.7 Hz, 1H,H₂), 3.935 (s, 1H, H₁), 4.203 (d, J=4.0 Hz, 1H, H₄), 2.072 (s, 3H,NCH₃).

EXAMPLE 50 Preparation of N-formamidinyl epibatidine dihydrochloride(45)

Scheme 6 shows the preparation of compound 45.

Racemic-epibatidine 19 (42 mg, 0.2 mmol) was mixed with 77 mg (0.7 mmol)freshly prepared ethyl formamidinate hydrochloride and 129 mg (1.0 mmol)diisopropyl ethylamine in 1 ml acetonitrile. After stirring at roomtemperature for 48 hours, the mixture was acidified with 1.0 M hydrogenchloride in ether. After evaporation in vacuo, the residue was separatedon silica gel preparative thin layer chromatography, using a solventsystem of 25% methanol in chloroform, to give 25 mg of the compound 45as a hygroscopic solid. Yield 36%. MS(CI), 236, 238 (free base M+1).H¹-NMR (CD₃OD). δ3.40 (M, 1H, H₂).

EXAMPLE 51

The process of Example 50 was repeated with the replacement of ethylformamidinate by S-methyl pseudothiourea, S-methyl-N-methylpseudothiourea, S-methyl-N-nitro pseudothiourea, or methyl acetamidinateto form the N-guanidyl, N-methyl-guanidyl, N-nitroguanidyl andN-acetamidinyl epibatidine.

EXAMPLE 52 Preparation of N-formamidinyl deschloroepibatidinedihydrochloride (46)

N-Formamidinyl epibatidine (12 mg, 0.04 mmol) 45 was dissolved in 2 mlmethanol containing 5 mg 10% palladium on carbon. After hydrogenationunder 1 atm hydrogen for 3 hours, the catalyst was removed byfiltration. The filtrate was concentrated in vacuo to give 10 mgcompound 46 as a hygroscopic solid. Yield 100%. MS(CI), 202(M+1−2HCl).H¹-NMR (CD₃OD), δ3.5 (M, 1H, H₂).

EXAMPLE 53 Preparation of 1-methyl epibatidine (47), and 4-methylepibatidine (48)

a) Preparation of 2-methylpyrrole (49)

2-Methylpyrrole was prepared according to the method set forth in J.Org. Chem. 28, 3052.

b) Preparation of N-t-butoxycarbonyl-2-methylpyrrole (50)

2-Methyl pyrrole (2.5 g) was dissolved in 6 ml tetrahydrofuran, and wasslowly added to a suspension of 2.4 g 60% sodium hydride (washed withether) in 30 ml tetrahydrofuran. A solution of 7.6 gdi-t-butyl-dicarbonate in 20 ml of the same solvent was added to thiscooled mixture. After shaking occasionally for 3 hours, it wasdecomposed carefully with water, and extracted with ether. The combinedorganic layer was washed with saturated brine and dried over magnesiumsulfate. Removal of the solvent gave 6 g residue. Bulb-to-bulbdistillation gave 4.5 g slightly yellow oil (ca. 80° C./5 mmHg). Yield80%. MS(CI), 183(M+2). H¹-NMR (CDCl₃) δ1.584 (s, 9H, 3CH₃), 2.421 (s,3H, CH₃).

c) Preparation of 1- (and 4)-methyl-2-(6-chloro-3-pyridyl)-3-phenylsulfonyl-7-t-butoxycarbonyl-7-azanorborna-2,5-diene(51)

Compound 50 (10 mmol, 1.8 g) was mixed with1-(6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene (22) 555 mg (2.0mmol). The mixture was heated at 78° C. in a tightly covered flask undernitrogen for 24 hours. The mixture was separated on silica gel columneluting with 25% of ethyl acetate in petroleum ether. After recovery of1.5 g of compound 50 and 120 mg compound 22, 636 mg of compound 51 wasobtained as a yellow oil. Yield 69.3%. ¹H-NMR showed that the oil is a2:1 mixture of 1-methyl isomer and 4-methyl isomer. MS(CI), 459, 461.(M+1). H¹-NMR (CDCl₃), (for major isomer): 1.37 (s, 9H, 3CH₃), 1.748 (s,3H, CH₃), 5.45 (d, J=3 Hz, 1H, H₄). (For the minor isomer), 1.346 (s,9H, 3CH₃), 1.958 (s, 3H, CH₃), 5.26 (d, 1H, J=3 Hz, H₁).

d) Preparation of N-t-Boc-1 (and 4) -methyl epibatidine (52)

Compound 51 (1.0 mmol, 459 mg) was dissolved in a mixture of 20 mlmethanol and 10 ml tetrahydrofuran. The solution was stirred and cooledto −20° C. To this solution was added 720 mg sodium dihydrophosphatefollowed by 1.5 g (6.0 mmol) 6% sodium amalgam. After stirring at roomtemperature for 2 hours, another 0.8 g of 6% sodium amalgam was addedand stirring was continued for another 2 hours. The excess reagent wasdecomposed by water, and the solution was decanted out. Afterconcentration of the solution at ambient temp in vacuo, the residue wasextracted with methylene chloride (4×15 ml). The combined organic layerwas washed with saturated brine and dried over magnesium sulfate. Afterremoval of solvent, the residue (372 mg) was hydrogenated under 1atmhydrogen in the presence of 8.4 mg platinum oxide for 2 hours. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo to a residue (360 mg). Separation took place on a silica gelcolumn eluting with 17% ethyl acetate in petroleum ether. 95 mg of theendo-isomers and 65 mg of the exo-isomers were obtained. Total yield50%. MS(CI), 323, 325(M+1). H¹-NMR (CDCl₃) (for exo isomer major), 2.78(dd, 1H, J=5.4 Hz, 7.8 Hz, H₂), 4.45 (t, 1H, J=4.5 Hz, H₄).

e) Preparation of 1-methyl epibatidine (47) and 4-methyl epibatidine(48)

The exo-isomer of compound 52 (65 mg) was dissolved in 5 ml methylenechloride. To this cooled solution (0° C.) was added 2.5 mltrifluoroacetic acid. The resulting pink solution was then stirred atroom temperature for 1.5 hours. After neutralization with 4.5 gpotassium carbonate in 10 ml water, the organic layer was separated andthe aqueous layer was extracted with methylene chloride. The combinedorganic layer was washed with saturated brine and dried over magnesiumsulfate. Removal of solvent and separation on silica gel preparativethin layer chromatography developing with a mixed solvent (ethylacetate, methylene chloride and ammonia in methanol) gave 6 mg of4-methyl epibatidine 48 and 12 mg 1-methyl epibatidine 47. Total yield40.2% MS(CI), 223, 225(M+1). H¹-NMR (CDCl₃), (for 1-methyl epibatidine,major, exo-isomer). δ2.657 (dd, J=4.8, 8.7 Hz, 1H, H₂), 3.694 (t, J=4.7Hz, 1H, H₄). (For 4-methyl epibatidine, minor exo-isomer): 2.887 (dd,J=4.7 Hz, 1H, H₂), 3.486 (d, J=4.5 Hz, 1H, H₁).

EXAMPLE 54 Preparation of 2-(2-fluoro-5-pyridyl)-7-azanorbornane (53)

a) Preparation of 1-(2-fluoro-5-pyridyl)-2-phenylsulfonyl ethanone (54)

The method set forth in Example 26 was used, replacing 6-chloronicotinylchloride with 6-fluoronicotinyl chloride (see Anderson et al; J. Med.Chem, 1990, 33(6) 1667), providing compound 54 as a white crystal, mp.127-128° C. Yield 72%. MS(CI), 280(M+1). H¹-NMR (CDCl₃). δ2.70 (s, 2H,CH₂).

b) Preparation of 1-(2-Fluoro-5-pyridyl)-2-phenylsulfonyl acetylene (55)

Use of the method set forth in Example 27 gave compound 55 in 62% yieldfrom compound 54 as a white solid. mp. 97-98.5° C. MS(CI) 262(M+1).

c) Preparation of7-carbomethoxy-2-(2-fluoro-5-pyridyl)-3-Phenylsulfonyl-7-azabicyclo[2.2.1]-hepta-2,5-diene(56)

Use of the method set forth in Example 29 gave compound 56 in 66% yieldplus 22% of recovered acetylene 55. Compound 56 is a white cubiccrystal, mp. 85-87° C. MS(CI) 387(M+1). H¹-NMR (CDCl₃), 3.446 (br.s.,3H, CH3), 5.459 (d, J=7.2 Hz, 2H, H_(1,4)).

d) Preparation of7-carbomethoxy-5-(2-fluoro-5-pyridyl)-7-azabicyclo[2.2.1]hept-2-ene (57)

Use of the method set forth in Example 30 gave compound 57 as a 1:2.5mixture of exo and endo isomers in a total yield of 64% from compound56. MS(CI) 249(M+1). H¹-NMR (CDCl₃), (for endo-isomer). 3.682 (s, 3H,OCH₃), (for exo-isomer), 3.655 (s, 3H, OCH₃).

e) Preparation of7-carbomethoxy-2-(2-fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (58)

Use of the method set forth in Example 31 gave compound 58 as acolorless oil in a yield of 93.3% from compound 57. MS(CI) 251(M+1).H¹-NMR (CDCl₃), (for endo-isomer), δ3.722 (s, OCH₃), (for exo-isomer)δ3.671 (s, 3H, OCH₃).

f. Preparation of 2-(2-fluoro-5-pyridyl)-7-azanorbornane (53)

The method set forth in Example 32 was used to produce 23 mg (16.2%) ofthe exo-isomer of compound 53 and 54.8 mg (38%) of the endo isomer ofcompound 53, as an oil from 185 mg of Compound 58 (0.74 mmol). MS(CI)193(M+1). ¹H-NMR (CDCl₃). δ2.763 (dd, J=0.8, 9.0 Hz, 1H, H₂), 3.532 (s,1H, H₁), 3.769 (t, J=3.6 Hz, 1H, H₄). (For endo-isomer). δ3.324 (dt,J=12 Hz, 5.7 Hz, 1H, H₂), 3.779 (q, J=5.1 Hz, 2H, H_(1,4)).

EXAMPLE 55 Preparation of 2-(2-chloro-3-pyridyl)-7-azanorbornane (59)

a) Preparation of 1-(2-chloro-3-pyridyl)-2-phenylsulfonyl ethanone (60)

Use of the method set forth in Example 26 gave compound 60 in 74% yieldfrom 2-chloronicotinyl chloride as white solid, mp. 103-104° C. MS(CI)296, 297(M+1). H¹-NMR (CDCl₃) δ4.871 (s, 2H, —CH₂—).

b) Preparation of 1-(2-chloro-3-pyridyl)-2-phenylsulfonyl acetylene (61)

Use of the method set forth in Example 27 gave compound 61 in 27% yieldfrom compound 60 as a white solid, mp. 90-94° C. MS(CI) 278, 280(M+1).

c) Preparation of7-carbomethoxy-2-(2-chloro-3-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hepta-2,5-diene(62)

Use of the method set forth in Example 29 gave compound 62 in 62.4% from61 as an oil. MS(CI) 403, 405(M+1). H¹-NMR (CDCl₃), δ3.612 (s, 3H,OCH₃). 5.429 (t, J=2.1 Hz, 1H), 5.497 (t, J=2.1 Hz, 1H).

d) Preparation of7-carbomethoxy-5-(2-chloro-3-pyridyl)-7-azabicyclo[2.2.1]hept-2-ene (63)

Use of the method set forth in Example 30, gave compound 63 as theexo-isomer, 12%, and the endo-isomer, 35%. MS(CI) 265, 267(M+1). H¹-NMR(CDCl₃) (for exo-isomer). δ3.66 (s, 3H, OCH₃), 6.502 (br.s. 2H,H_(5,6)). H¹-NMR (CDCl₃) (for endo-isomer). δ3.686 (s, 3H, OCH₃), 4.882,5.029 (2br.s. 2H, H_(1,4)). 5.88, 6.544 (2br.s., 2H, H_(5,6)).

e) Preparation of7-carbomethoxy-2-(2-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane (64)

Using the method set forth in Example 31, the exo-compound 63 washydrogenated to give compound 64 in quantitative yield. MS(CI) 267,269(M+1). H¹-NMR (DCCl₃) δ3.277 (dd, J=4.5, 8.4 Hz, 1H, H₂). 3.654 (s,3H, OCH₃).

f) Preparation of 2-(2-chloro-3-pyridyl)-7-azanorbornane (59)

Use of the method set forth in Example 32, gave compound 59 fromexo-compound 64, in 41% yield as an oil. MS(CI) 209, 211(M+1). H¹-NMR(CDCl₃) δ3.162 (dd, J=4.8, 8.7 Hz, 1H, H₂), 3.681 (s, 1H), 3.795 (t,J=3.6 Hz, 1H) (H₁, H₄).

EXAMPLE 56 Preparation of2-(2-chloro-4-pyridyl)-7-azabicyclo[2.2.1]heptane (65)

a) Preparation of 1-(2-chloro-4-pyridyl)-2-phenylsulfonylethanone (66)

Using the method set forth in Example 26, where 2-chloroisonicotinylchloride (see Anderson et al., J. Med. Chem. 1990, 33(b), 1667) was usedinstead of 6-chloronicotinyl chloride, compound 66 was obtained in 51%yield as a white crystal, mp. 124-125.5° C. (methanol). MS(CI) 296,298(M+1).

b) Preparation of 1-(2-chloro-4-pyridyl)-2-phenylsulfonyl acetylene (67)

Using the method set forth in Example 27, compound 67 was obtained in54% yield from compound 66 as a white crystal, mp. 78-79° C. MS(CI) 278,280(M+1).

c) Preparation of7-carbomethoxy-2-(2-chloro-4-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hepta-2,5-diene(68)

Using the method set forth in Example 29, compound 68 was obtained fromcompound 67 in 68% yield as a slightly brown oil. MS(CI) 403, 405(M+1).H¹-NMR (CDCl₃) δ3.502 (br.s. 3H, OCH₃), 5.420, 5.483 (25, 2H, H_(1,4)),7.065 (s, 2H, H_(5,6)).

d) Preparation of7-carbomethoxy-5-(2-chloro-4-pyridyl)-7-azabicyclo[2.2.1]hept-2-ene (69)

Using the method set forth in Example 30, compound 69 was obtained fromthe desulfonation of compound 68 in 13.6% yield as a 1:2 mixture of exo-and and endo-isomers. MS(CI) 265, 267(M+1). ¹H-NMR (CDCl₃), (forendo-isomer) δ3.682 (s, 3H, OCH₃), (for exo-isomer). δ3.665 (s, 3H,OCH₃).

e) Preparation of7-carbomethoxy-2-(2-chloro-4-pyridyl)-7-azabicyclo[2.2.1]heptane (70)

Using the method set forth in Example 31, compound 70 was obtained fromthe hydrogenation of compound 69 in 95% yield. MS(CI) 267, 269(M+1).¹H-NMR (CDCl₃) (for endo-isomer), δ3.694 (s, 3H, OCH₃), (forexo-isomer). δ3.655 (s, 3H, OCH₃).

f) Preparation of 2-(2-chloro-4-pyridyl)-7-azabicyclo[2.2.1]heptane (65)

Using the method set forth in Example 32, compound 65 was obtained fromthe deprotection of compound 70 in 23.6% (exo-isomer). MS(CI) 209,211(M+1). ¹H-NMR (CDCl₃), δ2.738 (dd, J=9.0, 5.1 Hz, 1H, H₂), 3.629 (d,J=2.4 Hz, 1H), 3.791 (br.s., 1H). Some endo-isomer can be isolated.

EXAMPLE 57 Preparation of disodium 7-epibatidinylphosphate (71)

Epibatidine (40.0 mg) was dissolved in 3 ml phosphorous oxychloride andthe mixture was refluxed for 3 hours in the absence of moisture. Theexcess reagent was removed in vacuo to give 100 mg 7-epibatidinylphosphoryl dichloride as a brown oily residue. To 28 mg of this residuein 2 ml tetrahydrofuran was added 2 ml 1M sodium hydroxide in ice bath.The mixture was stirred at room temperature for another 4 hours. Afterevaporation of the organic solvent, the aqueous solution was washed withethyl ether (2×5 ml). The aqueous layer was then evaporated in vacuo toca. 0.5 ml and left to stand at room temperature for several hours togive compound 71 as a white crystal. Yield 14 mg (80%). ¹H-NMR(D₂O)δ2.745 (p, J=4.5 Hz, 1H, H2), 3.723 (br.s., 1H), 3.920 (br.s., 1H).7.357 (d, J=8.4 Hz, 1H). 8.073 (dd, J=2.4, 8.4 Hz, 1H), 8.263 (d, J=2.4Hz, 1H). ³¹P-NMR (D₂O). 5.332. Chlorosulfonic acid or other N-sulfatereagents can be used in place of phosphorus oxychloride, under thesereaction conditions to prepare the N-sulfate derivative of epibatidineand analogs thereto.

EXAMPLE 58 Preparation of 2,3-dehydroepibatidine (72)

a) Preparation of7-carbo-t-butozy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hepta-2,5-diene(73)

Using the method set forth in Example 29, compound 73 was obtained fromthe Diels-Alder reaction of1-(2-chloro-5-pyridyl)-2-phenylsulfonylacetylene 22 withN-carbo-t-butoxy pyrrole (N-t-Boc-pyrrole) in 64% yield as a whitesolid. mp. 133-134° C. MS(CI) 445, 447(M+1).

b) Preparation of7-t-boc-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hept-2-ene(73)

Adduct 73 (445 mg) was dissolved in a mixture of 20 ml methanol and 10ml tetrahydrofuran containing 8 mg platinum oxide. After hydrogenationunder latm hydrogen for 3 hours, the catalyst was removed by filtration.The filtrate was concentrated in vacuo to give 440 mg residue. It wassolidified after trituration in methanol. Yield 98%. MS(CI) 447,449(M+1). H¹-NMR (CDCl3) δ1.266 (s, 9H, C(CH₃)₃), 4.905, 4.945 (2br.s.,2H, H2,4).

c) Preparation of2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hept-2-ene(75)

Using the method set forth in Example 53e, the t-Boc of compound 74 waseasily deprotected by trifluoro acetic acid at 0° C. to give compound 75in 95.4% yield as a white solid. MS(CI) 347, 349(M+1). H¹-NMR (CDCl₃)δ4.423 (d, J=4.2 Hz, 1H), 4.500 (d, J=3.6 Hz, 1H) (H_(1,4)).

d) Preparation of 2,3-dehydroepibatidine (72)

Compound 75 (365 mg) was desulfonated using the method set forth inexample 30 to give 23 mg of compound 72 as a colorless oil. Yield 19%.MS(CI) 207, 209(M+1). H¹-NMR (CDCl₃) δ4.323 (s, 1H, H₁), 4.574 (d, J=3.0Hz, 1H, H₄), 6.560 (d, J=2.4 Hz, 1H, H₃).

EXAMPLE 59 Preparation of Chloroethylepibatidine (76)

Using the method set forth in Example 44, epibatidine 19 was alkylatedwith 1-chloro-2-bromoethane to give compound 76 in a 35% yield as aclear oil. MS(CI) 271,273, 275(M+1). H¹-NMR (CDCl₃). δ3.225, 3.476 (25,2H, H_(1,4)), 3.568 (t, J=6.6 Hz, 2H).

EXAMPLE 60 Preparation of 2-(2-hydroxy-5-pyridyl)-7-azanorbornane (77)

Compound 53 (8.5 mg, 0.044 mmol) was dissolved in 1 ml tert-butanol. Tothis solution was added 1 ml 2M potassium hydroxide. After reflux for 20hours and evaporation of butanol, the mixture was adjusted with 1Mhydrochloric acid to pH 6-7. Evaporation of solvent in vacuo andpurification of product with silica gel preparative thin layerchromatography developing with 20% 7N ammonia methanol in chloroformgave 4.2 mg compound 77 as an oil. Yield 50%. MS(CI) 191(M+1). ¹H-NMR(CDCl₃) δ2.554 (br.s., 1H, H₂), 3.503; 3.743 (2br.s., 2H, H_(1,4)).

EXAMPLE 61 Preparation of 2-(2-methylthio-5-pyridyl)-7-azanorbornane(78)

Using the method set forth in Example 33, compound 78 was obtained in28% yield from sodium methylmercaptanide in ethanol as a colorless oil.MS(CI) 221, 223(M+1). ¹H-NMR(CDCl₃) δ2.542 (s, 3H, SCH3), 2.757 (dd,J=5.1, 8.7 Hz, 1H, H₂), 3.546, 3.781 (2br.s., 2H, H_(1,4)).

EXAMPLE 62 Preparation of 5,6-bis(trifluoromethyl) deschloroepibatidine(79)

Scheme 8 shows the preparation of compound 79.

a) Preparation of7-t-Boc-1,2-bis(trifluoromethyl)-7-azabicyclo[2.2.1]hepta-2,5-diene (80)

Compound 80 was prepared according to the procedure set forth in J.Leroy et al, Synthesis, 1982 313.

(b) Preparation of7-t-Boc-2,3-bis(trifluoromethyl)-5-(pyridyl)-7-azabicyclo[2.2.1]hept-2-ene(81)

Compound 80 (165 mg, 0.5 mmol) and 105 mg 3-iodopyridine (0.5 mmol) weredissolved in 1 ml dimethyl formamide containing 9 mg palladium acetate,21 mg triphenyl phosphine, 120 mg piperidine and 60 mg 88% formic acid.The mixture was stirred at 60-70° C. under nitrogen for 1.5 hours and atroom temperature overnight. The solvent was removed in vacuo and theresidue was partitioned between methylene chloride and water. Theorganic layer was separated and the aqueous layer was extracted withmethylene chloride. The combined organic layer was washed with saturatedbrine and dried over magnesium sulfate. After removal of solvent invacuo, the residue (218 mg) was separated in silica gel column elutingwith 20% ethyl acetate in petroleum, to give 48 mg unstable compound 81as a red oil. MS(CI) 409(M+1). Yield 23%. ¹H-NMR(CDCl₃) δ1.427 (s, 9H,OC(CH₃)₃), 2.974 (dd, J=4.2, 8.4 Hz, 1H, H₂), 4.906, 5.147 (2br.s., 2H,H_(1,4)).

The 5-(2-chloro-5-pyridyl) analog was obtained by replacing theiodopyridine in the above reaction with 2-chloro-5-iodopyridine.

c) Preparation of2,3-bis(trifluoromethyl)-5-pyridyl-7-azabicyclo[2.2.1]hepta-2-ene (82)

Using the method set forth in Example 53e, compound 81 was easilydeprotected with trifluoroacetic acid to give compound 82 in 90% yield.¹H-NMR (CDCl₃). δ2.02 (dd, J=8.4, 2.1 Hz, 2H, H₃), 2.88 (dd, J=4.8, 8.4Hz, 1H, H₂), 4.36, 4.63 (2br.s., 2H, H_(1,4)).

The 5-(2-chloro-5-pyridyl) analog was obtained in the manner set forthabove.

d) Preparation of 5,6-bis(trifluoromethyl)deschloroepibatidine (79)

Compound 82 was hydrogenated under high pressure of hydrogen, providingcompound 79.

5,6-Bis(trifluoromethyl) epibatidine was obtained in the manner setforth above.

C. Synthesis of 7-Aza-2-Heterocyclic-Bicyclo[2.2.1]Heptanes or Heptenes

The syntheses described herein can be used to prepare7-aza-2-heterocyclic-bicyclo[2.2.1]heptanes and heptenes. As describedabove, the dipolar cycloaddition of pentaamminesosmium-pyrrole complexesaffords 2-carbomethoxy-7-azanorbornanes which are useful startingmaterials for 7-aza-2-heterocyclic-bicyclo[2.2.1]heptanes and heptenes.Reactions of these esters with acetamidoxime affords7-aza-(1′,2′,4′-oxadiazoles)-bicyclo[2.2.1]heptanes and heptenes.Specific examples of these compounds are shown in Table 4. The analogous7-benzyl and 7-unsubstituted compounds can be synthesized from thecorresponding methyl esters described in Examples 66 and 67. Thecorresponding 3′-methyl-5′-2-(7-azanorbornyl) isoxazoles, can besynthesized via the reaction of the methyl esters such as those producedin Examples 72 and 73 with the dianion of acetone oxime.

TABLE 4

R₁ R₂ R₃ CH₃ exo-CH₂NHCOCH₃ H CH₃ exo-CH₂NHCOPh H CH₃ exo-CH₂NHCONHPh HCH₃

H CH₃

CH₃ CH₃

H CH₃

H CH₃

H CH₃

H ArCH₂ endo-COOCH₃ H H endo-COOCH₃ H

EXAMPLE 63 Preparation ofexo-2-acetamidomethyl-7-methyl-7-azabicyclo[2.2.1]heptane

A solution of the exo-2-aminomethyl-7-methyl-7-azabicyclo[2.2.1]heptaneformed Example 21 (27 mg, 0.19 mmol) in ether (3 mL) was treated withacetic anhydride (30 mg, 0.3 mmol). After 20 minutes, the reactionmixture was extracted with aqueous 10% Na₂CO₃. The organic phase wasdried over MgSO₄, filtered, and evaporated, affording 29 mg (82%) of thetitle product. ¹H NMR (CDCl₃) δ7.66 (br s, 1H, NH), 3.24-3.14 (m, 3H,overlap of CH₂N and H4), 3.06 (d, J=3.9 Hz, 1H, H1), 2.18 (s, 3H, CH₃N),1.91 (s, 3H, CH₃CO, 1.87-1.75 (m, 3H), 1.45 (m, 2H), 1.25 (m, 2H); ¹³CNMR (CDCl₃) δ170.5 (CO), 64.9 (CH), 61.5 (CH), 44.2 (CH₂), 40.6 (CH,C2), 35.3 (CH₂), 34.0 (CH₃N), 25.8 (CH₂), 25.4 (CH₂), 23.2 (CH₃).

EXAMPLE 64 Preparation ofexo-2-benzamidomethyl-7-methyl-7-azabicyclo[2.2.1]heptane

The procedure described in Example 63 was followed, replacing aceticanhydride with benzoyl chloride. Purification of the crude product bycolumn chromatography on silica gel (using ether containing 2% NH₄OH and8% methanol) afforded the title product in 71% yield. ¹H NMR (CDCl₃)δ9.16 (br s, 1H, NH), 7.86-7.4 (m, 5H, Ph), 3.5-3.3 (m, 3H overlap ofCH₂N and H4), 3.18 (d, J=3.6 Hz, 1H, H1), 2.32 (s, 3H, CH₃N), 1.99-1.91(m, 3H), 1.69-1.51 (m, 2H), 1.41-1.37 (m, 2H); ¹³C NMR (CDCl₃) δ167.4(CO), 134.8 (C), 130.9 (CH), 128.3 (CH), 126.8 (CH), 65.4 (CH), 61.4(CH), 44.8 (CH₂N), 40.0 (CH, C2), 35.4 (CH₂), 34.0 (CH₃), 25.6 (CH₂),25.7 (CH₂).

EXAMPLE 65 Preparation ofN-[exo-2-(7-methyl-7-azabicyclo[2.2.1]heptyl)methyl]-N¹-phenyl urea

The procedure described in Example 63 was followed, replacing aceticanhydride with phenyl isocyanate. Purification by column chromatographyon silica gel (ether containing 5% NH₄OH and 10% methanol) afforded thetitle product in 67% yield. ¹H NMR (CDCl₃) δ7.30-6.9 (m, 5H, Ph), 6.89(br s, 1H, NH) 3.3-3.2 (m, 3H, overlap of CH₂N and H4), 3.04 (d, J=3.3Hz, 1H, H1), 2.6 (br s, 1H, NH), 2.07 (s, 3H CH₃N), 1.86-1.81 (m, 3H),1.51-1.43 (m, 2H), 1.33-1.29 (m, 2H); ¹³C NMR (CDCl₃) δ156.6 (CO), 138.9(C), 129.0 (CH), 123.3 (CH), 121.0 (CH), 64.8 (CH), 61.4 (CH), 44.9(CH₂N), 41.4 (CH, C2), 35.2 (CH₂), 34.1 (CH₃), 25.8 (CH₂), 25.5 (CH₂).

EXAMPLE 66 Preparation ofexo-2,5′-(3′-methyl-1′,2′,4′-ozadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane

The procedure set forth in Carrol et al., J. Med. Chem, 1993 36, 2846was used to prepare this compound. Sodium hydride (27 mg, 1.1 mmol) wasadded to a solution of acetamidoxime (77 mg, 1.04 mmol, 5 eg) in THF (10mL) and the mixture was stirred and refluxed under nitrogen for 1 hour.Exo-2-carbomethoxy-7-methyl-7-azabicyclo[2.2.]heptane (34 mg, 0.2 mmol)and powdered molecular sieves (85 mg) were added to the mixture and thereaction was refluxed and stirred for an additional 3 hours. The mixturewas filtered, the cake was washed with THF, the filtrate was evaporated,and the residue was chromatographed on silica gel using 1% NH₄OH, and 3%methanol in ether. This provided the exo product as a colorless resin(12 mg, 31%). ¹H NMR (CDCl₃) δ3.66 (d, J=4.2 Hz, 1H, H1), 3.39 (t, J=4.2Hz, 1H, H4), 2.93 (dd, J=9.3, 5.1 Hz, 1H, H2), 2.36 (s, 3H), 2.3 (m,1H), 2.23 (s, 3H), 2.0-1.8 (m, 3H), 1.45 (m, 2H); ¹³C NMR (CDCl₃) δ182.3(C), 167.4 (C), 65.8 (CH), 61.5 (CH), 41.4 (CH), 36.3 (CH₂), 35.1(CH₃N), 26.8 (CH₂), 26.3 (CH₂), 12.0 (CH₃).

EXAMPLE 67 Preparation ofexo-2,5′-(3′-methyl-1′,2′,4′-oxadiazolyl)-1,4-dimethyl-7-azabicyclo[2.2.1]heptane

The procedure of Example 66 was used except thatexo-2-carbomethoxy-1,4-dimethyl-7-azabicyclo[2.2.1]heptane was used inplace of exo-2-carbomethoxy-7-methyl-7-azabicyclo[2.2.1]heptane. Theproduct was purified by prep. GC on a OV-17 column (180° C.). ¹H NMR(CDCl₃) δ3.30 (dd, 1H), 2.37 (s, 3H), 2.15 (dd, 1H), 1.90 (m, 1H),1.6-1.8 (5H), 1.44(s, 3H), 1.05 (s, 3H); ¹³C NMR (CDCl₃) δ181.9 (C),166.8(C), 68.1(C), 66.6 (C), 46.4 (CH), 45.9 (CH₂), 38.6 (CH₂), 37.0(CH₂), 20.6 (CH₃), 18.36 (CH₃), 11.5 (CH₃).

EXAMPLE 68 Preparation ofendo-2,5′-(3′-methyl-1′,2′,4′-oxadiazolyl)-7-methyl-7azabicyclo[2.2.1]heptane

The procedure of Example 67 was repeated in the absence of molecularsieves using 2.25 eq of acetamidoxime and 3 eq NaH. This provided of exoand endo isomers. The isomers were separated by preparative TLC (2.0 mmplate, 2% saturated NH3-methanol in ether; exo R_(f)=0.4, endoR_(f)=0.3) (isolated yields after chromatographic separation: 17%, 15%,respectively). Data for endo isomer: ¹H NMR (CDCl₃) δ3.61 (m, 2H,overlap of H1 and H2), 3.35 (t, J=4.5 Hz, 1H, H4), 2.40 (s, 3H), 2.36(s, 3H), 2.3 (m, 1H), 1.9 (m, 1H), 1.8 (m, 1H), 1.6 (m, 1H), 1.4 (m,1H), 1.15 (m, 1H); ¹³C NMR (CDCl₃) δ180.5 (C), 166.8 (C), 65.0 (CH),61.9 (CH), 37.9 (br, CH), 34.5 (NCH₃), 32.7 (br, CH₂), 28.1 (br, CH₂),23.6 (br, CH₂), 11.5 (CH₃).

EXAMPLE 69 Preparation ofexo-2,5′-(3′-[4′-methoxyphenyl]-1′,2′,4′-oxadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane

This compound was prepared using the procedure set forth in Example 68,replacing acetamidoxime with 4-methoxybenzamidoxime. ¹H NMR (CDCl₃) δ8.0(d, J=9 Hz, 2H), 6.96 (d, J=9 Hz, 2H), 3.89 (s, 3H, CH₃O), 3.77 (d,J=4.2 Hz, 1H, H1), 3.41 (t, J=4.2 Hz, 1H, H4), 3.00 (dd, J=8.1, 4.2 Hz,1H, H2), 2.47-2.38 (m, 1H), 2.24 (s, 3H, CH₃N), 2.04-1.85 (m, 3H),1.55-1.42 (m, 2H); ¹³C NMR (CDCl₃) δ181.8 (C), 167.9 (C), 161.7 (C),129.1 (CH), 119.5 (C), 114.1 (CH), 65.5 (CH), 61.1 (CH), 55.3 (CH₃O),41.2 (CH, C2), 35.6 (CH₂), 34.8 (CH₃N), 26.7 (CH₂), 26.1 (CH₂).

EXAMPLE 70 Preparation ofendo-2,2′-(5′-methyl-1′,3′,4′-oxadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane

This compound was prepared using the method set forth in Ainsworth etal., J. Org. Chem., 1966, 31, 3442. A mixture ofendo-2-carbomethoxy-7-methyl-7-azabicyclo[2.2.1]heptane (108 mg, 0.64mmol), ethanol (2 mL), and hydrazine hydrate (0.44 g, 13.8 eq) wasrefluxed for 14 hours and the volatiles were removed in vacuo. Theresulting crude hydrazide was refluxed in excess triethyl orthoacetate(0.86 g, 8.3 eq) for 18 hours. The mixture was acidified with HCl andthe unreacted orthoester was evaporated. The residue was made basic withNH₃-methanol, triturated with methylene chloride, and filtered to removethe insoluble NH₄Cl. The filtrate was evaporated, and the crude materialpurified by preparative TLC (ether containing 7% of saturatedNH₃-CH₃OH), providing 29 mg (24%) of the title product. ¹H NMR (CDCl₃)δ3.51-3.45 (m, 2H, overlap of H2 with H1 or H4), 3.31 (t, J=4.8 Hz, 1H,H4 or H1), 2.47 (s, 3H), 2.33 (s, 3H), 2.29-2.19 (m, 1H), 1.95 (m, 1H),1.86-1.74 (m, 1H), 1.68-1.59 (m, 1H), 1.46-1.38 (m, 1H), 1.22-1.14 (m,1H); ¹³C NMR (CDCl₃) δ168.5 (C), 164.3 (C), 65.6 (CH), 62.4 (CH), 37.5(br, CH), 35.1 (NCH₃), 32.8 (br, CH₂), 28.4 (br, CH₂, 23.8 (br, CH₂),11.4 (CH₃).

EXAMPLE 71 Preparation ofexo-2,2′-(5′-methyl-1′,3′,4′-oxadiazolyl)-7-methyl-7-azabicyclo[2.2.1]heptane

The endo isomer produced in Example 70 (21 mg, 0.11 mmol) was refluxedin methanol (1 mL) containing potassium hydroxide (20 mg, 0.3 mmol) for45 minutes. The methanol was evaporated, the residue was dissolved inwater, and the resulting mixture was extracted with methylene chloride.The extract was dried and evaporated, affording 10 mg of a 1:1 mixtureof exo and endo isomers. The isomers were separated using preparativeTLC (acetonitrile containing 10% NH₃-methanol), affording the titleproduct (3 mg, 15% based on recovered endo isomer). ¹H NMR (CDCl₃) δ3.59(d, J=3.9 Hz, 1H, H1), 3.37 (t, J=4.2 Hz, 1H, H4), 2.93 (dd, J=9.3, 5.1Hz, 1H, H2), 2.46 (S, 3H), 2.24 (s, 3H), 2.0-1.7 (m, 4H), 1.5-1.37 (m,2H).

EXAMPLE 72 Preparation of2-carbomethoxy-7-(3′,5′-dimethylbenzyl)-7-azabicyclo[2.2.1]heptane

The procedure used in the synthesis of2-carbomethoxy-7-methyl-7-azabicyclo[2.2.1]heptane was used to make thetitle compound from 3′,5′-dimethylbenzylpyrrole using the procedures setforth in Example 13 and 14. This title compound was obtained as a 1:3mixture of exo/endo isomers in 27% yield. Data for major (endo) product:¹H NMR (CDCl₃) δ7.0 (s, 2H), 6.9 (s, 1H), 3.85 (s, 3H), 3.53 (br s, 2H),3.35 (m, 2H), 3.13 (m, 1H), 2.4 (m, 1H), 2.35 (s, 6H) 2.0 (m, 1H),1.9-1.32(m, 4H).

EXAMPLE 73 Preparation of 2-carbomethoxy-7-azabicyclo[2.2.1]heptane

The product formed in Example 72 was treated with an equal weight of 10%Pd-on-C and refluxed in 96% formic acid for 12 hours. The mixture wasfiltered, the filtrate was partitioned between 10% aqueous Na₂CO₃ andmethylene chloride, and the extract dried and evaporated, affording a48% yield of the title compound. Major (endo) isomer: ¹H NMR (CDCl₃)δ4.12 (t, 1H), 3.92 (t, 3H), 3.8 (s, 3H), 3.2 (m, 1H), 2.3 (br s, 1H),2.2-1.55 (m, 6H).

FIG. 6 provides examples of a synthetic route for production of7-aza-2-isoxazole-bicyclo[2.2.1]heptane. This procedure is set forth indetail below in Examples 74 through 82.

EXAMPLE 74 Preparation of(+/−)-(exo)-7-(1,1-dimethylethoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one(83)

A procedure similar to that set forth in Dess et al. J. Org. Chem. 1983,48, 4156 was used prepare compound 83. The Dess-Martin periodinane (2.0g, 4.70 mmol) was added to a stirred solution of2-hydroxy-7-(1,1-dimethylethoxycarbonyl)-7-azabicyclo[2.2.1]heptane 82(1.0 g. 4.72 mmol). After 12 hours the mixture was diluted with Et₂O andpoured into saturated aqueous NaHCO₃ containing a sevenfold excess ofNa₂SO₃. The organic layer was washed with saturated aqueous NaHCO₃, withH₂O, dried over MgSO₄, filtered and concentrated. The resulting residuewas purified by chromatography 20% EtOAc/hexanes) to give compound 83(0.83 g, 84%) as a clear oil that solidified on standing.

EXAMPLE 75 Preparation of(+/−)-7-(1,1-dimethylethoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-ylidene(84)

A procedure similar to that set forth in Fitjer, et al., SyntheticCommunications 1985, 15 (10), 855 was used to prepare compound 84.Methyl triphenylphosphonium bromide (1.55 g, 4.34 mmol) was added to astirred solution of potassium tert-butoxide (0.53 g, 4.34 mmol) inabsolute benzene (8.0 mL). The mixture was refluxed for 15 minutes andmost of the solvent was evaporated off. Ketone 83 (0.83 g, 3.93 mmol)was added to the remaining slurry at 90° C. The reaction mixture wasstirred at 90° C. for 2 hours, cooled, and partitioned between H₂O (25mL) and Et₂O (80 mL). The aqueous layer was extracted with Et₂O (3×80mL). The combined organic layers were dried over MgSO₄, filtered andconcentrated. The resulting residue was purified by chromatography (10%EtOAc/hexanes) to give compound 84 (0.52 g, 63%) as a clear oil. R_(f)0.72 (10% EtOAc/hexanes). ¹H-NMR (CDCl₃, 300 MHz) δ4.93 (s, 1 H), 4.73(s, 1 H), 4.50-4.36 (m, 1 H), 4.34-4.20 (m, 1 H), 2.53-1.54 (m, 5 H)1.43 (s, 9 H).

EXAMPLE 76 Preparation of(+/−)-(exo)-7-(1,1-dimethylethoxycarbonyl)-2-hydroxymethyl-7-azabicyclo[2.2.1]heptane85

BH₃° (CH₃)₂S (1.75 mL, 2.0 M in THF) was added to a stirred, cooled (0°C.) solution of 84 (0.52 g, 2.49 mmol) in hexanes (6.0 mL). The coolingbath was removed. After 3 hours, ethanol (2 mL) was added followed by amixture of NaOH (3 mL, 3 M), and H₂O₂ (30%, 3 mL). The mixture washeated at 40° C. for 2 hours, cooled and partitioned between brine andEt₂O. The aqueous layer was extracted with Et₂O (3×25 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated to givecompound 85 as a clear oil. R_(f) 0.54 (50% EtoAc/hexanes). ¹H-NMR(CDCl₃, 300 MHz) δ4.34-4.00 (m, 2 H), 3.82-3.26 (m, 2 H), 3.00 (s, 1 H),2.51-2.28 (m, 1 H), 2.08-0.68 (m, 15 H).

EXAMPLE 77 Preparation of(+/−)-(exo)-7-(1,1-dimethylethoxycarbonyl)-2-formyl-7-azabicyclo[2.2.1]heptane(86)

A procedure similar to that set forth in Danishefsky et al. J. Org.Chem. 1991, 56, 2535 was used to preare compound 86. The Dess-Martinperiodinane (0.89 g, 2.09 mmol) was added to a stirred solution of 85(0.49 g, 2.17 mmol) and pyridine (0.62 g, 7.80 mmol). After 2 hours, themixture was diluted with Et₂O and poured into saturated aqueous NaHCO₃containing a sevenfold excess of Na₂S₂O₃. The organic layer was washedwith saturated aqueous NaHCO₃, with H₂O, dried over MgSO₄, filtered andconcentrated. The resulting residue was purified by chromatography (40%EtOAc/hexanes) to give the title compound 86 (0.22 g, 45%) as a clearoil and a mixture of isomeric aldehydes (0.8 g). R_(f) 0.86 (40%EtOAc/hexanes). ¹H NMR (CDCl₃, 300 MHz) δ9.79 (s, 1 H), 4.68-4.45 (m, 1H), 4.41-3.83 (m, 1 H), 3.17-2.94 (m, 1 H), 2.11-1.05 (m, 15 H).

EXAMPLE 78 Preparation of(+/−)-(exo)-2-[1′-(2′,2′-dibromo-1′-ethenyl)]-7-(1,1-dimethylethoxycarbonyl)-7-azabicyclo[2.2.1]heptane(87)

A procedure similar to that set forth in Corey, et al., TetrahedronLett. 1972, 3769 was used to prepare compound 87. Aldehyde 86 (0.22 g,0.98 mmol) dissolved in CH₂Cl₂ was added to a stirred, cooled (0° C.)solution of CBr4 (0.72 g, 2.17 mmol) and triphenylphosphine (1.05 g, 4.0mmol) in CH₂Cl₂ (5.0 mL). The reaction mixture was stirred 10 minutes,diluted with pentane and filtered through a Celite pad. The filter cakewas washed with Et₂O and the filtrate concentrated. The resultingresidue was purified by chromatography (a linear gradient of 0-10%Et₂O/pentane) to give compound 87 as a clear oil that solidified onstanding. R_(f) 0.75 (10% Et₂O/pentane). ¹H-NMR (CDCl₃, 300 MHz) δ6.35(d, J=8.7 Hz, 1 H) , 4.40-4.00 (m, 2 H), 3.05-2.80 (m, 1 H), 2.32-2.05(m, 1 H), 1.90-1.32 (m, 12 H).

EXAMPLE 79 Prepared of(+/−)-(exo)-2-(1,1′-ethynyl)-7-(1,1-dimethylethoxycarbonyl)-7-azabicyclo[2.2.1]heptane(88)

A procedure similar to that set forth in Corey, et al., TetrahedronLett. 1972, 3769 was used to prepare compound 88. n-BuLi(0.56 mL, 2.69 Min hexanes) was added to a stirred cooled (−78° C.) solution of thedibromide 87 (0.26 g, 0.68 mmol) in THF (7.0 mL). The reaction mixturewas stirred at −78° C. for 1 hour, warmed to room temperature, andstirred 1 hour more. The reaction was quenched by the addition of H₂Oand partitioned with Et₂O. The aqueous layer was extracted with Et₂O.The combined organic layers were dried over MgSO₄, filtered andconcentrated. The resulting residue was purified by chromatography (10%EtOAc/hexanes) to give compound 88 (0.16 g, 60%) as a clear yellow oil.R_(f) 0.75 (10% EtOA/hexanes). ¹H-NMR (CDClhd 3, 300 MHz) δ4.35-4.05 (m,2 H), 2.94-2.73 (m, 1 H), 2.28-1.97 (m, 2 H), 1.89-1.24 (m, 13 H).

EXAMPLE 80 Preparation of(+/−)-7-(dimethylethoxycarbonyl)-2-[5′-(3′-methyl)isoxazolyl]-7-azabicyclo[2.2.1]heptane(89)

A procedure similar to that set forth in Kozikowski et al. J. Org. Chem.1985, 50, 778 was used to prepare compound 89. A stirred solution of thealkyne 88 (0.16 g, 0.73 mmol), phenylisocyanate (0.69 g, 5.79 mmol),triethylamine (3 drops), and nitroethane (0.11 g, 1.45 mmol) in benzenewas heated at 75-85° C. for 16 hours. The reaction mixture was cooled,and filtered. The filtrate was partitioned between H₂O and hexanes. Theorganic layer was washed with saturated aqueous NaHCO₃, and with H₂O,dried over MgSO₄, filtered and concentrated. The resulting residue waspurified by chromatography (linear gradient of 10-20% EtOAc/hexanes) togive compound 89 (0.12 g, 60%) as a light yellow semisolid. R_(f) 0.33(10% EtOAc/hexanes). ¹H-NMR (CDCl₃, 300 MHz) δ5.89 (s, 1 H), 4.50-4.37(m, 1 H), 4.34-4.24 (m, 1 H), 3.50-3.37 (m, 1 H), 2.45-1.16 (m, 18H)ppm.

EXAMPLE 81 Preparation of 2-[5′-(3′-methyl)isoxazolyl]-7-azabicyclo[2.2.1]heptane, (90)

Trifluoroacetic acid (1.49 g, 13.0 mmol) was added to a stirred, cooled(0° C.) solution of the isoxazole 89 (56.4 mg, 0.212 mmol) in CHCl₃ (2mL). After stirring for 18 hours, the volatile components wereevaporated and the remaining residue partitioned between saturatedaqueous K₂CO₃ and CHCl₃. The aqueous layer was extracted with CHCl₃. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated to give compound 90 (41.2 mg, 69%) as a clear oil thatformed a wax-like solid upon standing. The product could be furtherpurified by chromatography (10% CH₃OH/CHCl₃). R_(f) 0.33 (10%CH₃OH/CH₂Cl₂). ¹H-NMR (CDCl₃, 300 MHz) δ5.92 (s, 1 H), 4.10-3.87 (m, 2H), 3.63-3.13 (m, 2 H), 2.42-2.11 (m, 4H), 1.89-1.32 (m, 5 H).

EXAMPLE 82 Preparation of2-[5′-(3′-methyl)isoxazolyl]-7-methyl-7-azabicyclo[2.2.1]heptane (91)

A procedure similar to that set forth in Garvey et al. J. Med Chem.1994, 37, 1055 was used to prepare compound 91. A stirred solution ofthe isoxazole 90 (19.3 mg, 0.18 mmol), formalin (0.32 mL, 37% in H₂O),and formic acid (0.22 mL, 88% in H₂O) was heated at 85-90° C. for 20hours. The mixture was cooled to room temperature, treated with HCl (6M)and extracted with Et₂O. The aqueous layer was basified with saturatedaqueous K₂CO₃ and extracted with CHCl₃. The combined organic layers weredried over MgSO₄, filtered, and concentrated. The resulting residue waspurified by chromatography (10% CH₃OH/CH₂Cl₂) to give compound 91 (11. 5mg, 55%) as an oil. R_(f) 0.52 (10% CH₃OH/CH₂Cl₂). ¹H-NMR (CDCl₃, 300MHz) δ5.89 (s, 1 H), 3.63-3.24 (m, 3 H), 2.58-2.08 (m, 7 H), 1.97-1.13(m, 5H).

EXAMPLE 83 Preparation of(+/−)-(exo)-7-(methoxycarbonyl)-2-(2′-quinolyl)-7-azabicyclo[2.2.1]heptane(92)

A procedure similar to that set forth in Regen, et al., TetrahedronLett. 1993, 7493 was used to prepare compound 92.N-Methoxycarbonyl-7-azabicyclo[2.2.1]heptene was added to a stirredsolution of palladium acetate (5.6 mg, 0.0249 mmol), triphenylphosphine(12 mg, 0.046 mmol), piperidine (90 mg, 0.11 mmol), formic acid (38 mg,0.83 mmol), and 2-iodoquinoline (21.8 mg, 0.86 mmol) in DMF (0.3 mL).The mixture was heated at 75° C. for 7 hours cooled, and partitionedbetween EtOAc (30 mL) and H₂O (10 ml). The organic layer was washed withH₂O (3×10 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated. The resulting residue was purified by chromatography(linear gradient of 20-40% EtOAc/hexanes) to give compound 92 (45.4 mg,49%) as an oil. R_(f) 0.33 (40% EtOAc/hexanes). ¹H-NMR (CDCl₃, 300 MHz)δ9.00-7.45 (m, 6 H) , 4.84-4.05 (m, 2 H), 3.64 (s, 3 H), 3.29-2.95 (m,1H), 2.34-1.42 (m, 6 H).

EXAMPLE 84 Preparation of(+/−)-(exo)-2-(2′-quinolyl)-7-azabicyclo[2.1.1]heptane (93)

A solution of 92 (45.4 mg, 0.168 mmol) in 33% HBr [(con.) in HOAc (con9.0 ML)] was stirred for 30 hours. The solvent was evaporated and theresulting solid residue was dissolved in H₂O. The aqueous solution wasbasified with NaOH (2 N) and extracted with CH₂Cl₂ (4×10 mL). Thecombined organic layers were dried over MgSO₄, filtered andconcentrated. The resulting residue was purified by chromatography (5%CH₃OH saturated with NH₃/CH₂Cl₂) to give compound 93 (21.5 mg, 60%) asan oil. R_(f) 0.28 (5% CH₃OH saturated with NH₃/CH₂Cl₂). ¹H-NMR (CDCl₃,300 MHz) δ9.03-7.37 (m, 6 H), 4.00-3.57 (m, 2 H), 3.10-2.87 (m, 1 H),2.32-1.13 (m, 7H).

EXAMPLE 85 Preparation of(+/−)-(exo)-7-methyl-2-(2′-quinolyl)-7-azabicyclo[2.2.]heptane (94)

A procedure similar to that set forth in Garvey et al J. Med. Chem.1994, 37, 1055 was used to prepare compound 94. A stirred solution ofthe quinoline 93 (12.5 mg, 0.059 mmol), formalin (0.32 mL, 37% in H₂O),and formic acid (0.22 mL, 88% in H₂O) was heated at 85-90° C. for 20hours. The mixture was cooled to room temperature, treated with HCl (6M)and extracted with Et₂O. The aqueous layer was basified with saturatedaqueous K₂CO₃ and extracted with CHCl₃. The combined organic layers weredried over MgSO₄, filtered, and concentrated. The resulting residue waspurified by chromatography (10% CH₃OH/CH₂Cl₂) to give compound 94 (9.3mg, 70%) as an oil. R_(f) 0.32 (10% CH₃OH/CH₂Cl₂). ¹H-NMR (CDCl₃, 300MHz) δ8.97-7.89 (m, 6 H), 3.63-3.39 (m, 2 H), 3.11-2.92 (m, 1 H), 2.45(s, 3 H), 2.29-1.00 (m, 6 H).

EXAMPLE 86 Preparation of 2-(5′-oxazole)-7-methyl-7-azanorbornane (95)

2-Carbomethoxy-7-methyl-7-azanorbornane is obtained as set forth inExample 15. The compound is chromatographed on a silica gel column toseparate the exo- and endo- isomers.

Exo-2-carbomethoxy-7-methyl-7-azanorbornane is reacted with lithiomethylisocyanide (the Schollkopf Reaction), as disclosed by Jacobi, P. A. etal., J. Org. Chem. 1981, 46, 2065, to produce2-(5′-oxazole)-7-methyl-7-azanorbornane 95. This process is set forth inFIG. 3.

EXAMPLE 87 Preparation of2-(1′,3′,4′-oxadiazole)-7-methyl-7-azanorbornane (96)

2-Carbomethoxy-7-methyl-7-azanorbornane is obtained as set forth inExample 15. The compound is chromatographed on a silica gel column toseparate the exo- and endo-isomers.

Exo-2-carbomethoxy-7-methyl-7-azanorbornane is reacted using theprocedure disclosed by Ainsworth, C. et al., J. Org. Chem. 1966, 31,3442 to form the 2-(1′,3′,4′-oxadiazole)-7-methyl-7-azanorbornane. Thisreaction occurs by cyclizing an ethoxymethylene hydrazide intermediatewith triethyl orthoformate, to produce the2-(1′,3′,4′-oxzdiazole)-7-methyl-7-azanorbornane 96.

EXAMPLE 88 Preparation of 2-(tetrazole)-7-methyl-7-azanorbornane (97)

2-Cyano-7-methyl-7-azanorbornane is obtained as set forth in Example 16.The compound is chromatographed on a silica gel column to separate theexo- and endo-isomers.

Exo-2-cyano-7-methyl-7-azanorbornane is converted in one step to thetetrazole 97, as shown in FIG. 4, using the procedures described byKadaba, P. K. Synthesis 1973, 71.

EXAMPLE 89 Preparation of 2-(imidazole)-7-methyl-7-azanorbornane (98)

2-Cyano-7-methyl-7-azanorbornane is obtained as set forth in Example 16.The compound is chromatographed on a silica gel column to separate theexo- and endo-isomers.

Exo-2-cyano-7-methyl-7-azanorbornane is converted to the imidate esterintermediate 99, as shown in FIG. 4, using the Pinner reaction, asdescribed by Patai, S., ed. The Chemistry of Amidines and Imidates,Wiley, 1975.

The imidate ester intermediate 99, is then converted to the the2-substituted imidazole 98, as shown in FIG. 4, using the reactiondisclosed by Lawson, A., J. Chem. Soc. 1957, 4225.

EXAMPLE 90 Preparation of 2-(benzopyrimidinone)-7-methyl-7-azanorbornane(100)

2-Cyano-7-methyl-7-azanorbornane is obtained as set forth in Example 16.The compound is chromatographed on a silica gel column to separate theexo- and endo-isomers.

Exo-2-cyano-7-methyl-7-azanorbornane is converted to the imidate esterintermediate 99, as shown in FIG. 4, using the Pinner reaction, asdescribed by Patai, S., ed. The Chemistry of Amidines and Imidates,Wiley, 1975.

The imidate ester intermediate 99, is then converted to the the2-substituted benzopyrimidinone 100 using the reaction disclosed byRied, W. et al, Chem. Ber. 1962, 95, 3042, as shown in FIG. 4.

EXAMPLE 91 Preparation of 2-(acylamino)-7-methyl-7-asanorbornane and2-(acylaminomethyl)-7-methyl-7-asanorbornane

Either exo-2-cyano-7-methyl-7-azanorbornane or theexo-2-carbomethoxy-7-methyl-7-azanorbornane is converted to theexo-2-amino intermediate 101, as shown in FIG. 5. The exo-2-aminocompound 101 may either be reacted to form heterocyclic rings, or may beacylated to provide open chain analogs, such as 102 and 103, as shown inFIG. 5. For example, the Hoffman rearrangement, using the method ofWallis, E. S. et al., Org. Reactions 1946, 3, 267, of the amide obtainedby mild alkaline hydrolysis of the nitrile, or the Schmidt reaction ofthe corresponding acid, using the method of Wolff, H. Organic Reactions1946, 3, 307, yields the the exo-2-amine 101. Alternatively,hydrazinolysis of the exo-2-carbomethoxy compound, followed by amodified Curtius rearrangement may be used to prepare the carbamate 104,as shown in FIG. 5.

Alternatively, the 2-cyano moiety is reduced with lithium aluminumhydride to yield exo-2-aminomethyl compound 105, which may be acylatedto give amide or carbamate open chain compounds 106.

Pharmaceutical Compositions

Humans, equine, canine, bovine and other animals, and in particular,mammals, suffering from disorders characterized by increased ordecreased cholinergic function, as described in more detail herein, canbe treated by administering to the patient an effective amount of one ormore of the above-identified compounds or a pharmaceutically acceptablederivative or salt thereof in a pharmaceutically acceptable carrier ordiluent. The active materials can be administered by any appropriateroute, for example, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, in liquid, cream, gel or solid form.

As used herein, the term pharmaceutically acceptable salts or complexesrefers to salts or complexes that retain the desired biological activityof the above-identified compounds and exhibit minimal undesiredtoxicological effects. Nonlimiting examples of such salts are (a) acidaddition salts formed with inorganic acids (for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, andthe like), and salts formed with organic acids such as acetic acid,oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid,benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid,naphthalenesulfonic acid, naphthalenedisulfonic acid, andpolygalacturonic acid; (b) base addition salts formed with metal cationssuch as zinc, calcium, bismuth, barium, magnesium, aluminum, copper,cobalt, nickel, cadmium, sodium, potassium, and the like, or with acation formed from ammonia, N,N-dibenzylethylene-diamine, D-glucosamine,tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and(b); e.g., a zinc tannate salt or the like.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount without causing serious toxic effectsin the patient treated for any of the disorders described herein. Apreferred dose of the active compound for all of the herein-mentionedconditions is in the range from about 0.0001 to 20 mg/kg, preferably0.001 to 2 mg/kg per day, more generally 0.05 to about 0.5 mg perkilogram body weight of the recipient per day. A typical topical dosagewill range from 0.001% to 0.5% wt/wt in a suitable carrier. Theeffective dosage range of the pharmaceutically acceptable derivativescan be calculated based on the weight of the parent compound to bedelivered. If the derivative exhibits activity in itself, the effectivedosage can be estimated as above using the weight of the derivative, orby other means known to those skilled in the art.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing 0.001 to 1000 mg,preferably 0.01 to 500 mg of active ingredient per unit dosage form. Aoral dosage of 0.1 to 200 mg is usually convenient.

The active ingredient can be administered by the intravenous injectionof a solution or formulation of the active ingredient, optionally insaline, or an aqueous medium or administered as a bolus of the activeingredient.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at is varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring. When the dosageunit form is a capsule, it can contain, in addition to material of theabove type, a liquid carrier such as a fatty oil. In addition, dosageunit forms can contain various other materials which modify the physicalform of the dosage unit, for example, coatings of sugar, shellac, orother enteric agents.

The active compound or pharmaceutically acceptable salt or derivativethereof can be administered as a component of an elixir, suspension,syrup, wafer, chewing gum or the like. A syrup may contain, in additionto the active compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The active compound or pharmaceutically acceptable derivatives or saltsthereof can also be mixed with other active materials that do not impairthe desired action, or with materials that supplement the desiredaction, such as antibiotics, antifungals, antiinflammatories, orantiviral compounds.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic. If administered intravenously, preferredcarriers are physiological saline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation.

Analgesic Activity of 7-Azabicyclo[2.2.1]-heptanes and -heptenes

A wide variety of biological assays have been used to evaluate theability of a compound to act as an analgesic. Any of these known assayscan be used to evaluate the analgesic ability of the compounds disclosedherein. The Straub-tail reaction, which is characteristic of opiatealkaloids, has been used as an assay for opiate agonists andantagonists. The assay is described in detail in Br. J. of Pharmacol.1969, 36, 225. Another accepted assay for analgesic activity is the hotplate analgesia assay, described in J. of Pharmacol. Exp. Therap. 1953,107, 385. An assay for the evaluation of the ability of a compound tobind to an opiate receptor is described in Mol. Pharmacol. 1974, 10,868.

In addition to their potent central analgesic effects, some of thesubstituted 7-aza-bicyclo[2.2.1]-heptanes and -heptenes described hereinalso possess varying degrees of peripheral anti-inflammatory andanalgesic effects which are useful for therapeutic applications. Thefollowing assays for the evaluation peripheral anti-inflammatoryactivities are described in Barber, A. and Gottschlich, R., OpioidAgonists nd Antagonists: An Evaluation of Their Peripheral Actions inInflammation, Medicinal Research Review, Vol. 12, No.5, 525-562(September, 1992) : paw hyperalgesia in rat that has been induced byprostaglandin E2 or carrageenan; inflamed knee joint in cat that hasbeen induced by carrageenan, bradykinin or PGE₂; formalin test in mouseor rat that has been induced by formalin; neurogenic inflammation inrat, cat or guinea pig that has been induced by antidromic stimulationof sensory nerves; and the writhing test in mouse that is induced byacetic acid, phenylbenzoquinone, prostaglandin or bradykinin; andadjuvant arthritis in rat that is induced by Freund's adjuvant.

EXAMPLE 86 Evaluation of Analgesic Activity

Table 5 provides the analgesic activity measured as ED₅₀ (μg/Kg) forselected compounds disclosed herein, as determined using the Straub-Tailassay, as describe by J. Daly et al. J. Am. Chem. Soc., 1980, 102, 830;T. F. Spande, et al. J. Am. Chem. Soc. 1992, 114, 3475; T. Li, et al.Bioorganic and Medicinal Chemistry Letters 1993, 3, 2759.

TABLE 5 ED₅₀ Structural formula μg/Kg Comments

9 (μg/Kg) 1-epibatidine 7.5 d-epibatidine

>100

<10

10000 Mixture of endo and exo isomers (1.3:1)

750

100% @ 1000 (μg/Kg)

<1000

250

<1000

100˜200

ca. 50

ca. 100

ca. 10

10 racemic

99% @ 100

ca. 1000

EXAMPLE 87

Evaluation of Nicotinic Receptor Binding Activity

7-Aza-bicyclo[2.2.1]-heptanes and -heptenes were evaluated for theirability to bind to the acetylcholine nicotinic receptor using a standardbinding assay, e.g. X. Zhang and A. Nordberg, Arch. Pharmacol., 348, 28(1993); R. E. Middleton and J. B. Cohen, Biochemistry, 30, 6987 (1991),with nicotine sulfate as the reference compound, rat cortex as thetissue substrate, and a [³H]-NMCI radioligand. The results are providedin Table 6.

TABLE 6 Testing Inhibition Structural Formula Level %

10⁻⁷ M 10⁻⁹ 10⁻¹¹ 106  72  13 10⁻⁷ 10⁻⁹ 10⁻¹¹ 102  77  10

10⁻⁷ 10⁻⁹ 10⁻¹¹ 102  22  5

10⁻⁵ 10⁻⁷ 10⁻⁹ 104 103 103

10⁻⁵ M 10⁻⁷ 10⁻⁹ 104 100  49

10⁻⁷ 10⁻⁹ 10⁻¹¹ 104  49  22

10⁻⁷ M 10⁻⁸ 10⁻⁹ 103.9  71.3  5

R = H R = CH₃ 10⁻⁵ M 10⁻⁷ 10⁻⁵ 103  24  81

EXAMPLE 88 Competition with Cytisine for Binding to Rat Cortex (Brain)Receptors

[³H](−)-Cytisine is a nicotinic cholinergic receptor ligand that bindswith high affinity to the a4b2 subtype receptor, the major subtype inrodent brain accounting for >90% of (−)-nicotine binding sites (Flores,et al., 1992; Whiting, et al., 1992). This nicotinic receptor subtype ismost sensitive to (−)-nicotine compared to other receptor subtypes(Connolly, et al., 1992). Compounds that compete with cytisine for thenicotinic cholineric receptor are considered nicotine receptor agonists.

A membrane fraction from rat brain cortex (Harlan Laboratories) wasprepared using an adaptation of an established method (Pabreza, et al.,1991). Compound and [³H]-(−)-cytisine (New England Nuclear, 42 Ci/mmol)were mixed before addition of membrane (0.5 mg protein) and incubated inglass tubes for 75 minutes on ice; total assay volume was 0.24 ml.Parallel assays to determine nonspecific binding were incubated in thepresence of 10 uM (−)-nicotine (Sigma). Bound radioactivity was isolatedby vacuum filtration onto glass microfiber filters (Whatman, GF-B) usingmillipore tubs, followed by 3×4 ml buffer wash. Filters were prerinsedwith 0.5% polyethyleneimine prior to sample filtration to reducenonspecific binding. Bound radioactivity was quantitated byscintillation counting.

Tables 7 and 8 provide the nicotine receptor IC₅₀ in nanomolarconcentration for selected compounds.

TABLE 7 Nicotine Receptor Tail-Flick Cytisine Assay ED₅₀ % Effect IC₅₀After 5 and 60 min. Structure (nM) (mg/kg)

32,000 −2.9 −3.6

  150   6.7 24.6

TABLE 8 Nicotine Receptor Tail-Flick IC₅₀ Assay ED₅₀ Structure (nM)(mg/kg)

100 0.230

630 >2,000

 24 ˜1,000

 77 —

 7 >2,000

EXAMPLE 89 Tail-Flick Assay in Mice and Rats

Female CD-1 mice (20-25 g, Charles River Labs) and male CD rats (300-400g, Charles River Labs) were housed in groups of two and five,respectively. Animals were given food and water ad libitum. Most studieswere performed using groups of 5 animals per treatment unless otherwisenoted.

Antinociceptive effects (i.e., analgesia) of test compounds in mice andrats were measured by the tail-flick test using a tail-flick analgesiameter (EMDIE Instrument Co.). A maximum latency of 10 sec was imposed ifno response occurred within that time. Antinociceptive activity,measured as % MPE, was calculated as [(test−control)/(10−control)×100)].

Duration of compound and (−)-nicotine-induced antinociception wasassessed in mice by measuring antinociception at 2, 5, 10, 20 min aftercompound (20 μg/kg, s.c.) or nicotine (5 mg/kg, s.c.).

Mice (7/group) or rats were pretreated i.v. (0.9% saline or antagonist,mecamylamine, hexamethonium, atropine, naloxone or yohimbine) 10 minutesbefore administration of compound or nicotine at different doses. Acontrol response (1.5-4 sec) was determined for each animal beforetreatment and test latencies were assessed at 5 minutes after compoundadministration (5 ml/kg, s.c.) or 2 min after nicotine (5 ml/kg, s.c.).

Tables 6 and 7 provide the tail-flick data for selected compounds.

IV. Identification and Use of Nicotinic and Muscarinic Agonists andAntagonists

Methods for the determination of the specific cholinergic receptoractivity profile for a selected compound is easily determined usingknown assays. For example, to determine which type or types ofacetylcholinergic receptors a compound is interacting with, in vitrocompetitive binding assays can be performed using specific radioligands.A compound's ability to compete with a specific radioligand for receptorbinding indicates an affinity for that receptor type. Radiolabellednicotine (or cytisine) and quinuclidinyl benzilate are commonly used fornicotine and muscarinic receptor types, respectively. However, whetheror not the compound is an agonist or antagonist is typically notdetermined by these assays.

To differentiate between agonists or antagonists, cell, tissue oranimal-based in vitro or in vivo assays are typically employed. Fornicotinic receptor ligands, one assay involves treating an animal withcompound, then measuring a pharmacological activity associated withnicotinic receptor agonism, such tail-flick analgesia. If compoundtreatment resulted in analgesic activity, the compound is considered anicotinic agonist. The compound's agonist activity should also beblocked by known nicotinic receptor antagonists. A similar protocol canbe utilized if a cell-based assay, such as release of dopamine fromstriatal synaptosomes, is used.

If there is no nicotinic agonist activity, e.g. analgesia, in thisexample, after compound treatment, an effective dose of a knownnicotinic agonist (such as nicotine) is subsequently given to thecompound-treated animal. If the compound is an antagonist with theability to block the effects of a known agonist, then the resultinganalgesic activity would be less than that expected for the given doseof agonist.

Muscarinic agonists/antagonists can be characterized using appropriatemuscarinic receptor-mediated in vitro and in vivo assays. Pharmacologicapproaches can include, for example, include receptor-mediatedmobilization of Ca⁺² in cultured cells, depolarization of the ratesuperior cervical ganglion, or contraction of the longitudinal musclemyenteric-plexus preparation of the guinea pig.

Compounds which act as nicotinic receptor agonists are useful in thetreatment of cognitive neurological and mental disorders, includingParkinson's disease, Tourette's Syndrome, Alzheimer's disease, attentiondeficit disorder, dementia, multi-infart dementia, vascular dementia,cognitive impairment due to organic brain disease including due toalcoholism and brain diseases, general problems with informationprocessing, deficient regional cerebral blood flow and cerebral glucoseutilization, psychiatric disorders (e.g., schizophrenia and depression),as well as other conditions such as analgesia, ulcerative colitis,aphthous ulcer, cessation of smoking, body weight loss and treatment ofthe symptoms of anxiety and frustration associated with withdrawal fromother addictive substances, such as, cocaine, diazepam or alcohol.Nicotinic receptor agonists can also be used for veterinary purposes,including as respiratory stimulants, ectoparasiticides, andanthelmitics.

Compounds which act as nicotinic receptor antagonists are useful asganglion-blocking agents, in the control of blood pressure inhypertension, in autonomic hyperreflexia regulation, in the control ofhypotension during surgery and in the reduction of bleeding duringoperations. These compounds can also be used as stabilizingneuromuscular blocking agents which are extensively used as adjuvants inanesthesia for the relaxation of skeletal muscles, treatment for severemuscle spasms and ventilatory failure from various causes such asobstructive airway disorders. In addition, nicotinic receptorantagonists are useful as depolarizing neuromuscular blocking agents,for example, as skeletal muscle relaxants in endotracheal intubation orpsychiatric electroshock therapy to prevent muscle and bone damage.Nicotine antagonists are also useful in blocking both the secretagogueand mitogenic effects of nicotine on cancer cells such as human smallcell lung carcinoma. Finally, nicotine antagonists can be used asantidotes for curare/nicotine poisoning.

Muscarinic receptor agonists are widely used for ophthalmic purposes,for example, in the treatment of glaucoma to reduce intraocularpressure, applied alone or in combination with β-adrenergic blockingdrugs or sympathomimetic agents, or for the treatment of accomodativeesotropia. These agonists are also useful for one or more of thefollowing indications: breaking adhesions between the iris and the lens;for the treatment of various disorders involving the depression ofsmooth muscle activity without obstruction (postoperative atony,congenital megacolon); in stimulating smooth muscle activity in theurinary and gastrointestinal tract; in reflux esophagitis, in thetreatment of postoperative atonia of the stomach or bowel; for gastricretention following bilateral vagotomy; for congenital megacolon andcombating esophageal reflux; in the treatment of urinary retention andinadequate emptying of the bladder postoperatively or post partum; andin the treatment of memory disorders and cognitive functions ofAlzheimer's patients. The efficacy and side-effects of muscarinicreceptors may be improved by optimizing their differential activity onvarious muscarinic receptor subtypes, e.g., M1 vs. M2/M3 receptors, asdescribed by Showell, G. A., et al., Medicinal Chemical Research, 1993,3:171-177.

Muscarinic receptor antagonists (antimuscarinic agents) are widely usedin ophthalmology to produce mydriasis and/or cycloplegia. Selective Mlreceptor antagonists are effective in treating peptic ulcer disease, andin the inhibition of gastric acid secretion. Antimuscarinic agents arealso useful in treating increased tone or motility of thegastrointestinal tract, such as diarrheas, and in combating biliary andrenal colics frequently in combination with an analgesic drug.Antimuscarinic agents, including quaternary ammonium compounds, areuseful in treating obstructive pulmonary diseases such as chronicbronchitis or bronchial asthma. Cardioselective antimuscarinic agentsare useful in treating symptomatic sinus bradycardia, e.g., in acutemyocardial infarction, higher degree heart block and certain types ofventricular arrhythmias. Muscarinic receptor antagonists are also usedin preoperative medication to counteract the vegal effects, to reduceexcessive bronchial secretion, and to produce some sedation and amnesia.Centrally acting antimuscarinic agents are useful in the treatment ofParkinson's disease, by restoring the normal balance of cholinergic anddopaminergic neurotransmission in the basal ganglia, in the preventionof motion sickness, as a sedative, to relieve the symptoms of myastheniagravis, in the antagonism of skeletal muscle relaxant effects ofneuromuscular blocking agents, and in the treatment of poisoning bycholinesterase inhibitors such as those used in insecticides andchemical warfare. Such compounds are also useful to counteractanaesthesia effects, and in mushroom poisoning.

The clinical efficacy and safety of muscarinic receptor antagonists canbe optimized by adjusting tissue selectivity, receptor subtypespecificity and a balance of antagonism and agonism vs. differentreceptor subtypes, as well as by selective local (topical, aerosol, eyedrop) or systemic administration of the drug.

Modifications and variations of the present invention will be obvious tothose skilled in the art from the foregoing detailed description of theinvention. Such modifications and variations are intended to come withinthe scope of the appended claims.

We claim:
 1. The compound having the structure: 